The IgG2a Ig subclass plays a critical role in the pathogenesis of humoral autoimmunity and protection against pathogens. The T‐box transcription factor T‐bet has been implicated as a critical mediator of class‐switch recombination (CSR) to IgG2a, but its relative importance to this process in various immune contexts remains incompletely defined. We report here that, surprisingly, T‐bet is selectively required for IgG2a class switching in response to T‐independent, but not T‐dependent, stimuli. Specifically, T‐dependent signaling through CD40, in contrast to T‐independent signaling via lipopolysaccharide, can bypass a requirement for T‐bet in IgG2a germline transcription and subsequent isotype switching. In contrast, T‐bet‐deficient B cells undergo class switching to other IgG isotypes at least as well as wild‐type counterparts. Thus, T‐bet is a class‐specific regulator of IgG CSR and represents a unique regulator of B cell differentiation by participating in a T‐independent, but not a T‐dependent, activation pathway. T‐bet‐deficient B cells therefore represent a novel paradigm by which to investigate the regulation of humoral immune responses.