Background &Aims: The intestinal lamina propria has traditionally been viewed as the effector site of mucosal immune responses. However, this view has been challenged with the identification, in the murine lamina propria, of an in situ class switch DNA recombination pathway to IgA. In this study, we tested the hypothesis that in situ class switching occurs in the human lamina propria. Methods: Immunohistochemistry was used to analyze tissue microenvironments and RT-PCR to look for molecular evidence of Ig class switching and to track clonally related cells of B lineage. Results: We found no evidence of proliferation of either lamina propria CD20+or CD19+cells or evidence of activation-induced cytidine deaminase mRNA expression outside the organized gut-associated lymphoid tissue, although Iα-Cαimmunoglobulin germ-line gene transcript expression could be identified in the lamina propria. We identified clonally related cells, including IgA and IgM isotype-switched variants, in multiple samples known to be free of activation-induced cytidine deaminase, organized lymphoid tissue, or cellular proliferation. For 4 groups of cells, the patterns of somatic mutations on the rearranged IgVH5 gene segment were more similar between cells from distant sites than from their immediate neighbors, implying dissemination of cells from a common set of precursors. Conclusions: Our data are inconsistent with a model in which precursors of human IgA-secreting plasma cells are induced or expanded in the lamina propria. The human lamina propria is therefore likely to solely be an effector site of intestinal secretory IgA responses that originate from the organized gut-associated lymphoid tissues. Background & Aims: The intestinal lamina propria has traditionally been viewed as the effector site of mucosal immune responses. However, this view has been challenged with the identification, in the murine lamina propria, of an in situ class switch DNA recombination pathway to IgA. In this study, we tested the hypothesis that in situ class switching involved in the human lamina propria. Methods: Immunohistochemistry was used to analyze tissue microenvironments and RT-PCR to look for molecular evidence of Ig class switching and to track clonally related cells of B lineage . Results: We found no evidence of proliferation of either lamina propria CD20 + or CD19 + cells or evidence of activation-induced cytidine deaminase mRNA expression outside the organized gut-associated lymphoid tissue, although Iα-Cαimmunoglobulin germ-line gene transcript expression could be identified in the lamina propria. We identified clonally related cells, including IgA and IgM isotype-switched variants, in multiple Samples 4 to 4 groups of cells, the patterns of somatic mutations on the rearranged IgVH5 gene segments were more similar between cells from distant sites than from their immediate neighbors , implying dissemination of cells from a common set of precursors. Conclusions: Our data are inconsistent with a model in which precursors of human IgA-secreting plasma cells are induced or expanded in the lamina propria. The human lamina propria is therefore likely to solely be an effector site of intestinal secretory IgA responses that originate from the organized gut-associated lymphoid tissues.