Interferon and its inducers are known to depress drug biotransformation in vivo by decreasing the levels of cytochrome P-450 (P450) monooxygenase system in the liver. However, very little is known about the effects of interferon on P450 in extrahepatic tissues. In this study we investigated the effects of a recombinant human interferon-alpha (rhIFN-alpha) on aryl hydrocarbon hydroxylase (P450IAI) in cultured human peripheral lymphocytes (HPL). Non-induced and induced (3-methylcholanthrene) mitogen activated lymphocytes were used throughout the study. rhIFN-alpha maximally depressed AHH activity to approximately 58% of control after 24 hrs of incubation in both non-induced and induced lymphocytes. However, after 48 hrs of incubation with rhIFN-alpha, AHH activity had recovered to 86% of control in induced cells and 61% in non-induced cells. rhIFN-alpha had no significant effect on either NADH cytochrome c reductase activity or on viable lymphocyte cell count. This is the first demonstration that rhIFN-alpha can have a direct depressive effect on a P450 dependent monooxygenase system in HPL.