It is unknown how lifetime marijuana use affects different proinflammatory cytokines. The purpose of the current study is to explore potential differential effects of lifetime marijuana use on interleukin-1 alpha (IL-1α) and tumor necrosis factor (TNF) in a community based sample. Participants included 168 African American adults (51 % female, median age = 47 years). Upon study entry, blood was drawn and the participants completed questions regarding illicit drug use history whose answers were used to create three groups: lifetime non-drug users (n = 77), lifetime marijuana only users (n = 46) and lifetime marijuana and other drug users (n = 45). In the presence of demographic and physiological covariates, non-drug users were approximately two times more likely (AOR 2.73, CI 1.18, 6.31; p = .03) to have higher TNF levels than marijuana only users. Drug use was not associated with IL-1α. The influence of marijuana may be selective in nature, potentially localizing around innate immunity and the induction of cellular death.