Both primary IgM and secondary IgM and IgG adoptive immune responses to the thymus-independent antigen NIP-POL were found to proceed in two stages. The first 3 to 4 days of these responses required a stimulus, but this could be provided by an unrelated antigen such as HRC. Only the second 3- to 4-day stage of the response, leading to an AFC peak at day 8, required the specific antigen NIP-POL. This novel priming schedule of nonspecific followed by specific antigenic stimulation in fact produced a significantly greater AFC response than the standard specific immunization procedure. With the schedule of nonspecific, then specific antigen injection, the primary IgM response was T cell independent. Two sequential injections of specific antigen also gave an elevated adoptive response from the same B cell subset, but this time the increased component of the response was T cell dependent. The results corroborate earlier work, and support a model of two sequentially related and “antigen”-responsive subsets of both primary and secondary B cells, termed “pre-progenitors” and “direct AFC progenitors”. Responses to antigens are thus two-tiered. In the first stage, all “pre-progenitor” subsets are nonspecifically activated to proliferate and differentiate into “direct-progenitor” B cells. This stage is different from “pre-B” to B cell development. Although it may occur continuously at a lower level in normal animals, it requires an environmental or experimentally introduced stimulus, and is probably triggered via macrophage activation. In the second stage the conventional rules apply, and antigens specifically stimulate antigen-restricted clones of direct-progenitor B cells to produce AFC.