delta 9-Tetrahydrocannabinol (THC) exposure suppresses multiple immunological functions of macrophages. The ability of macrophages exposed to THC to process and present soluble protein antigens was investigated by the stimulation of antigen-specific helper T cell hybridomas to secrete interleukin-2. The T cell response to hen egg lysozyme was dramatically reduced after a 24-hr pretreatment of a macrophage hybridoma with THC. In contrast, THC exposure did not alter the capacity of the macrophage hybridoma to process chicken ovalbumin and augmented their presenting cell function for a pigeon cytochrome c response. These findings could not be attributed to differential effects of THC on either cell viability or expression of the antigen receptor-associated CD3 complex by the T cells. The level of T cell activation with peptides of lysozyme and cytochrome c, which do not require processing, was inhibited only at the highest concentrations of THC, suggesting that THC mainly affects antigen processing. Peritoneal macrophages exposed to THC during an antigen pulse and fixed with paraformaldehyde showed similar effects on the subsequent T cell responses to lysozyme and cytochrome c in the absence of THC, arguing against a possible influence of THC on the T cells. Therefore, THC differentially modulates the capacity of macrophages to process antigens that is necessary for the activation of CD4+ T cells.