Orthoclone OKT3 (Ortho Biotech Inc, Raritan, NJ) is a potent immunosuppressive agent effective in the therapy of acute renal allograft rejection. Following the first one or two doses, patients often exhibit a "flu-like" illness ascribed to OKT3-induced release of cytokines. Systemic reactions resulting from the cytokines include pyrexia, pulmonary edema, bronchospasm, photophobia, headache, hypotension, rigors, hypertension, gastrointestinal disturbances, and arthralgias/myalgias. The cyclooxygenase inhibitor indomethacin has been shown to ameliorate the pyrexia associated with OKT3 administration. We conducted a retrospective analysis with the purposes of (1) confirming that indomethacin reduces pyrexia and (2) determining the effect of indomethacin on the other aforementioned adverse side effects. Group 1 patients (n = 28) received indomethacin during the initial 48 hours of OKT3 antirejection therapy. Group 2 patients (n = 28) received OKT3 without indomethacin. The incidence of fever (P < 0.0001), headache (P < 0.030), and gastrointestinal disturbances (P < 0.030), and the number of adverse effects (P < 0.0001) were significantly less in the indomethacin-treated group. There were no differences between the groups in pre- and post-OKT3 serum creatinine levels. The indomethacin was well tolerated. We conclude that the widely available and relatively inexpensive cyclooxygenase inhibitor indomethacin safely and significantly reduces adverse effects associated with OKT3 therapy of acute renal allograft rejection.