Apoptosis is critical to B cell maturation, but studies of apoptotic regulation in primary human B cells is lacking. In this study, we sought to better understand the mechanisms of apoptotic regulation in normal and activated B cells. Using intracellular BH3 profiling, we defined the Bcl2 dependency of B cell subsets from human peripheral blood and tonsillar lymphoid tissue as well as mitogen-activated B cells. We found that naive and memory B cells were BCL-2-dependent, whereas germinal center B cells were MCL-1-dependent and plasma cells were BCL-XL-dependent. B cells stimulated to proliferate ex vivo by CpG or CD40L/IL-4 became more dependent on MCL-1 and BCL-XL As B cell lymphomas often rely on survival mechanisms derived from normal and activated B cells, these findings offer new insight into potential therapeutic strategies for lymphomas.