The lymphocyte response to phytohemagglutinin (PHA) as measured by [13H]thymidine incorporation is equally inhibited by 10(-5) to 10(-4) M concentrations of delta8, and delta9-tetrahydrocannabinol (THC), their 11-hydroxymetabolites, cannabidiol, cannabinol, cannabichromene, cannabicyclol. A similar inhibiting effect is produced by olivetol, which has the structure of the C ring common to all of these cannabinoids and their metabolites that accumulate in tissues. THC inhibits intracellular and intramolecular incorporation of thymidine, uridine, and leucine. This inhibition can be observed within 15 min after addition of THC to the culture medium. The cytotoxicity of THC is a function of the concentration of serum in the culture medium. The higher the concentration of serum, the more the cells are protected against the toxicity of THC. The cytotoxicity of THC is reversible by washing, after the cells have been incubated for 24 hr with the drug. Lymphocytes incubated with THC or olivetol present a significantly larger number of hypodiploid cells and a significant increase in segregational errors of chromosomes. The inhibitory effect of THC on macromolecular synthesis might be mediated by an alteration of the plasma membrane by the drug.