SummaryCyclooxygenase (Cox) inhibitors are among the most widely used and commonly prescribed medications. Relatively little is understood about their influence on human immune responses. Herein, we discovered a novel and important mechanism whereby non‐steroidal anti‐inflammatory drugs (NSAIDs) blunt human B‐cell antibody production. We demonstrate that the Cox‐2 selective small molecule inhibitors SC‐58125 and NS‐398 attenuate the production of human antibody isotypes including immunoglobulin M (IgM), IgG1, IgG2, IgG3 and IgG4. In addition, inhibition of Cox‐2 significantly reduced the generation of CD38+ IgM+ and CD38+ IgG+ antibody‐secreting cells. Interestingly, we discovered that inhibition of Cox‐2 activity in normal human B cells severely reduced the messenger RNA and protein levels of the essential plasma cell transcription factor, Blimp‐1. These observations were mirrored in Cox‐2‐deficient mice, which had reduced CD138+ plasma cells and a near loss of Blimp‐1 expression. These new findings demonstrate a critical role for Cox‐2 in the terminal differentiation of human B lymphocytes to antibody‐secreting plasma cells. The use of NSAIDs may adversely influence the efficacy of vaccines, especially in the immunocompromised, elderly and when vaccines are weakly immunogenic.