The role of membrane cofactor protein (MCP, CD46) on human T cell activation has been analyzed. Coligation of CD3 and CD46 in the presence of PMA or CD28 costimuli enhanced IL‐2, IFN‐γ, or IL‐10 secretion by CD4+ T lymphocytes. The effect of CD46 on IL‐10 secretion did not require additional costimuli like anti‐CD28 antibodies or phorbol esters. CD46 also enhanced IL‐2 or IFN‐γ secretion by CD4+ blasts. In contrast, IL‐5 secretion was inhibited upon CD46‐CD3 coligation, in all the cells analyzed. These effects were independent of IL‐12 and suggest that CD46 costimulation promotes a Th1‐biased response in human CD4+ T lymphocytes. CD46 enhanced TCR/CD3‐induced tyrosine phosphorylation of CD3ζ and ZAP‐70, as well as the activation of the ERK, JNK, and p38, but did not modify intracellular calcium. The effect of specific inhibitors shows that enhanced ERK activation contributes to augmented IFN‐γ and lower IL‐5 secretion and, consequently, to the Th1 bias. Cross‐linking CD46 alone induced weak tyrosine phosphorylation of CD3ζ and ZAP‐70. However, CD46 cross‐linking by itself did not induce cell proliferation or lymphokine secretion, and pretreatment of CD4+ T lymphocytes with anti‐CD46 antibodies did not significantly alter TCR/CD3 activation.