Dose-response relationships for anti-CD3 monoclonal antibody (mAb) therapy remain undefined, particularly with respect to higher dose ranges. The clinical efficacy and safety of an OKT3 dosing regimen that incorporates higher doses (escalating dose regimens) was examined in a pilot trial. Patients undergoing acute rejection were treated with a 7-d course of OKT3 in which the daily OKT3 dose was escalated during treatment course (daily doses 5, 5, 5, 5, 10, 15, 25 mg). The total amount of OKT3 given was equal to a standard 14-d course (70 mg). A total of 10 primary cadaveric renal transplant recipients were treated, and data analyzed from a median follow up of 5 months (range 3-13 months). Pre-OKT3 immunosuppressive therapy consisted of ATGAM induction therapy (n = 8), and corticosteroid rejection therapy (n = 6, 18.6 +/- 11.4 mg/kg). Median time of first rejection was 32 d (12-48 d) and median time to OKT3 was 33 d (range 15-42 d). Pre-OKT3 histology (by Banff criteria) included: mild ACR (n = 6), moderate ACR (n = 2), AVR (n = 1), ACR and acute transplant glomerulopathy (n = 1). Rejection reversal rate with escalating dose OKT3 was 100%, and each patient experienced a rapid reversal of rejection (i.e. reversal within 14 d initiation of OKT3 therapy). Six recurrent rejection episodes were diagnosed in 5 patients with a median time to recurrent rejection of 30 d following cessation of OKT3 therapy. All recurrent rejection episodes were successfully treated (FK 506 n = 4, corticosteroids n = 1, and OKT3 n = 1). CMV disease was limited to a single episode of CMV viremia in one patient. PTLD was observed in one patient who had coexisting vascular rejection at the time of PTLD diagnosis. Short- and long-term graft function is excellent (pre-rejection baseline creatinine 1.8 +/- 0.4 mg/dl, current creatinine 1.75 +/- 0.4 mg/dl). Monitoring of OKT3 serum levels revealed that patients maintained therapeutic serum levels for an average of 4 d following the last OKT3 dose. Circulating CD3+ and CD5+ cells were maintained below baseline levels for at least 10 d following the last OKT3 dose. Anti-OKT3 antibody formation occurred in 22% of patients, however, anti-idiotypic responses were of low titer. Adverse reactions experienced during dose escalation were minimal compared to first dose reactions, and consisted primarily of mild headaches and arthralgias in a minority of patients. OKT3 EDR, by obviating monitoring and administration costs, are cost effective [OKT3 EDR $8088, OKT3 SDR (10 d) $9684, OKT3 SDR (14 d) $13,224]. In conclusion, escalating dose regimens of OKT3: 1) provide rejection reversal rates similar to standard dose regimens, 2) provide high OKT3 serum levels and reliable CD3+ cell depletion, 3) induce minimal adverse reactions during dose escalation, and 4) may decrease costs by obviating the need for monitoring peripheral blood T cells and by decreasing administration costs and outpatient visits.