Context: Early response to multiagent chemotherapy, including mercaptopurine, as measured by minimal residual disease is an important prognostic factor for c hildren with acute lymphoblastic leukemia (ALL). Thiopurine methyltransferase (T PMT) is involved in the metabolism of mercaptopurine and subject to genetic poly morphism, with heterozygous individuals having intermediate and homozygous mutan t individuals having very low TPMT activity. Objective: To assess the associatio n of TPMT genotype with minimal residual disease load before and after treatment with mercaptopurine in the early treatment course of childhood ALL. Design, Set ting, and Patients: TPMT genotyping of childhood ALL patients (n = 814) in Germa ny consecutively enrolled in the ALLBFM (Berlin- Frankfurt- Mü nster) 2000 study from October 1999 to September 2002. Minima l residual disease was analyzed on treatment days 33 and 78 for riskadapted trea tment stratification. A 4- week cycle of mercaptopurine was administered betwee n these 2 minimal residual disease measurements. Patients (n = 4) homozygous for a mutant TPMT allele, and consequently deficient in TPMT activity, were treated with reduced doses of mercaptopurine and, therefore, not included in the analys es. Main Outcome Measures: Minimal residual disease load before (day 33) and aft er (day 78) mercaptopurine treatment. Loads smaller than 10- 4 were defined as negative. Results: Patients (n = 55) heterozygous for allelic variants of TPMT c onferring lower enzyme activity had a signifi- cantly lower rate of minimal res idual disease positivity (9.1 % ) compared with patients (n = 755) with homozyg ous wild- type alleles (22.8% ) on day 78 (P = .02). This translated into a 2. 9- fold reduction in risk for patients with wild- type heterozygous alleles (r elative risk, 0.34; 95% confidence interval, 0.13- 0.86). Conclusions: TPMT g enotype has a substantial impact on minimal residual disease after administratio n of mercaptopurine in the early course of childhood ALL, most likely through mo dulation of mercaptopurine dose intensity. Our findings support a role for minim al residual disease analyses in the assessment of genotypephenotype associations in multiagent chemotherapeutic trials. Context: Early response to multiagent chemotherapy, including mercaptopurine, as measured by minimal residual disease is an important prognostic factor for c hildren with acute lymphoblastic leukemia (ALL). Thiopurine methyltransferase (T PMT) is involved in the metabolism of mercaptopurine and subject to genetic poly morphism, with heterozygous individuals having intermediate and homozygous mutan t individuals having very low TPMT activity. Objective: To assess the associa n of TPMT genotype with minimal residual disease load before and after treatment with mercaptopurine in the early treatment course of childhood ALL. Design , Set ting, and Patients: TPMT genotyping of childhood ALL patients (n = 814) in Germa ny consecutively enrolled in the ALLBFM (Berlin-Frankfurt-Münter) 2000 study from October 1999 to September 2002. Minima l residual disease was analyzed on treatment days 33 and 78 for riskadapted trea tment stratification. A 4- week cycle of mercaptopurine was administe red betwee n these 2 minimal residual disease measurements. Patients (n = 4) homozygous for a mutant TPMT allele, and caused deficient in TPMT activity, were treated with reduced doses of mercaptopurine and, therefore, not included in the analys es. Main Outcome Measures: Minimal residual disease load before (day 33) and aft er (day 78) mercaptopurine treatment. Loads smaller than 10-4 were defined as negative. Results: Patients (n = 55) heterozygous for allelic variants of TPMT c onferring lower enzyme activity had a signifi- cantly lower rate of minimal residual disease positivity (9.1%) compared with patients (n = 755) with homozygous wild-type alleles (22.8%) on day 78 (P = .02) a 2. 9-fold reduction in risk for patients with wild-type heterozygous alleles (r elative risk, 0.34; 95% confidence interval, 0.13- 0.86). Conclusions: TPMT g enotype has a substantial impact on minimal residual disease after administratio n of mercaptopurine in the ear ly course of childhood ALL, most likely through mo dulation of mercaptopurine dose intensity. Our findings support a role for minim al residual disease analyzes in the assessment of genotype phenotype associations in multiagent chemotherapeutic trials.