Whether the risks of acute rejection after elective cyclosporine (CsA) withdrawal in renal transplantation outweigh the potential benefits is unclear. We examined results for 236 patients who underwent transplantation between January 1986 and June 1991. Patients were treated with prophylactic CsA, prednisone, and azathioprine, and had grafts that functioned at least 1 year. We elected to withdraw CsA after 1 year in 192 patients who were rejection free for 12 months. Thirty-four patients elected to continue CsA. In 1988 a protocol that tapered CsA over 6 weeks was abandoned when eight (29.6%) of the first 27 patients developed acute rejection within 6 months. We then adopted a 12-week CsA taper preceded by 1 month of increased azathioprine (2.5 mg/d as tolerated) and followed by increased prednisone (30 mg/d for 1 week, 20 mg/d for 1 week, 15 mg/day for 6 months, then 15 mg/d on alternate days). With this protocol the incidence of postwithdrawal acute rejection within 6 months was reduced to 9.1% among 165 patients (P < 0.01 v 6-week taper). Actuarial 5-year graft survival (patients living with a functioning graft) was 81.7% for patients left on CsA, 88.9% for patients tapered over 6 weeks, and 81.5% for patients tapered over 12 weeks (P > 0.05). We also examined risk factors for acute rejection after CsA withdrawal using a Cox proportional hazards model and found that the relative risk of acute rejection within 6 months of taper was approximately two times greater for each DR mismatch (P < 0.001). We conclude that CsA withdrawal has not affected renal allograft survival at our center.(ABSTRACT TRUNCATED AT 250 WORDS)