Although it is known that elective cyclosporine (CsA) withdrawal increases the risk for acute rejection, few studies have been large enough to identify risk factors for acute rejection after CsA withdrawal. We examined risk factors for acute rejection in 464 kidney transplant recipients who underwent elective CsA withdrawal. The incidence of acute rejection within 6 months of CsA withdrawal was 20/141 (14.2%) in the period January 1986 to May 1989, but only 14/323 (4.5%) since May 1989 (p = 0.0002). Among those transplanted since May 1989, the incidence was 5/20 (25%) for those with both 2 HLA-B and 2 HLA-DR mismatches, compared with only 9/298 (3.0%) for those with fewer mismatches (p < 0.0001). In Cox proportional hazards analysis, risk factors for acute rejection within 6 months, or at any time after elective CsA withdrawal, were date of transplant January 1986 to May 1989 (compared with more recently May 1989 to March 1999), younger age, obesity, as well as B and DR mismatches. Recipient race (83% were white), acute rejection during the first year before withdrawal (31%), mycophenolate mofetil (17%), and other variables failed to predict postwithdrawal acute rejection. We concluded that avoiding CsA withdrawal in the relatively small number of recipients with both 2 HLA-B and 2 HLA-DR mismatches could further reduce our already low incidence of acute rejection following elective CsA withdrawal.