The synthesis of anti-human serum albumin (HSA) antibody was induced in the absence of added antigen in lymphoid cells obtained from CBA mice that had been immunized weeks to months earlier. This response was restricted to cells or tissue fragments obtained from lymphoid organs in the lymphatic drainage path of the original site of antigen administration. Injection of 125I-HSA revealed that retained antigen was likewise restricted to the spleen and draining lymph nodes and that it was present in these organs for long periods of time. Autoradiography indicated that within the limits of detection, antigen was further restricted to cells within the lymphoid follicles and was not retained in macrophages of the medulla, the subcapsular sinus, or the superficial cortex. Small fragments of lymph nodes placed in organ culture showed that the spontaneous response corresponded with the presence of follicular antigen. The more antigen present in a fragment the greater the spontaneous response. The belief that retained radioactivity represented active immunogen, even 7 weeks after injection, was supported by the observation that it could be specifically depleted from the lymphoid follicles by injecting nonradioactive HSA. On the basis of these data it appears likely that antigen retained in lymphoid follicles remains active for prolonged periods and stimulates antibody synthesis whenever antibody levels decline. Thus, retained follicular antigen could play a major role in the mechanism which maintains and regulates serum antibody levels for months or years after immunization.