The immunosuppressive effect of feline leukemia virus (FeLV) and its 15,000 dalton envelope protein (p15E) were studied to determine if the mechanism of action was due to an increase in prostaglandin production. We examined the effects of exogenous PGE1 and PGE2 on the normal Con A response of feline peripheral blood lymphocytes (PBL) and found them to be inhibitory. The addition of the cyclooxygenase inhibitor indomethacin to cells incubated with FeLV or FeLV p15E and Con A completely abrogated the viral suppressive effects. This reversal was titratable and time-dependent. Other non-steroidal anti-inflammatory (NSAI) drugs were found to have similar actions. Indomethacin was also able to increase the suppressed Con A response of PBL from FeLV-infected cats. Upon measurement of PGE2 levels from PBL cultured with FeLV, we found a decrease in PGE2 accumulation associated with FeLV presence during the first 24 h of culture. These findings indicate that FeLV does not cause its immunosuppressive effects by increasing PG production and suggests that indomethacin and the other tested NSAI drugs do not produce their effect by PG inhibition.