Significance Immunoglobulins exist in several forms, or isotypes, that carry out distinct effector functions. During an antibody response, B cells can switch their immunoglobulin isotype through the process of class-switch recombination (CSR). CSR to IgD is a rare event compared with CSR to other isotypes, and its regulation is poorly understood. Here we report that mice lacking the DNA damage-response protein 53BP1 display a hyper-IgD syndrome despite deficiencies of other immunoglobulin classes. By studying these mice, we discovered that CSR to IgD in 53BP1 mutant mice and in wild-type mice depends on an intact microbiome and Toll-like receptor signaling, and is anatomically confined to B cells of mucosa-associated lymphoid tissues.