Exposure to drugs, either ethical pharmaceuticals or illicit street drugs, often results in medical complications, including alterations in the immune system. Among the drugs associated with immunomodulatory potential are the analgesics fentanyl and meperidine. The purpose of this study was to determine the potential of these drugs to alter immunological parameters subsequent to in vitro exposure at a range of concentrations. This potential immunotoxicity was assessed using a series of in vitro assays measuring B-lymphocyte proliferation, cytokine production by T-helper lymphocytes, T-lymphocyte cytolytic function, natural killer (NK) cell function, and macrophage function. Exposure to these analgesics was associated with a differential suppression of interleukin-4 production by T-cells, as well as a more generalized suppression of cytokine production by macrophages. In addition, T-cell cytolytic activity was suppressed at high drug concentrations. B-cell proliferation and NK cell activity were also inhibited, but to a lesser degree than noted with T-cell function. Addition of naltrexone to the cultures did not reverse these alterations in immune function, suggesting that these changes are not mediated via opioid receptors.