The proliferative response of phytohemagglutinin (PHA)- and interleukin 2 (IL-2)-activated murine splenocytes was studied in the presence of phencyclidine (PCP), a potent psychotomimetic drug of abuse. PCP inhibited [3H]-thymidine incorporation in lymphocytes treated with PHA or IL-2. This inhibitory action was dependent upon the drug doses and the time of incubation with the cultures. There was no significant inhibitory activity of PCP when it was added 24 hrs or 48 hrs after mitogenic stimuli. Parallel, a lower inhibitory effect was observed when IL-2 or PHA were simultaneously present in the incubation medium. Moreover, the pretreatment for 18 hrs with IL-2 completely counteracted PCP-induced depression of PHA-stimulated lymphocytes. We suggest that PCP affects some pathway that regulates the activation of resting T cells rather than affecting already cycling cells.