Simultaneous kidney-pancreas (SKP) transplantation is associated with increased risk of kidney rejection (KR) due to an unknown mechanism. The aim of this study is to analyze the characteristics of KR in 44 SKP transplantations under quadruple immunosuppressive therapy and to evaluate the response to treatment and its effect on renal allograft survival and renal function. The mean follow-up was 25 +/- 14 months. Seventy-seven percent of the patients (34 of 44) presented an acute renal allograft rejection. Sixty-six percent (29 of 44) had one rejection episode and 11% (5 of 4) 2 episodes. KR was early (85% in the first month after transplantation), intense (3.7-fold increase in creatinine) and had great clinical features. Twenty-eight percent of the patients had an early relapse during the first month after treatment. KR did not affect the survival of the renal allograft in the short-term (1 and 2 years). Overall, 62% were corticosensitive (CS) and the remaining 38% were corticoresistant (CR). The group with an isolated rejection without relapse was CS in 69% of the cases, achieved complete remission in 73% and renal function was not affected at 1 and 2 years [115 +/- 26 mumol/l (1.3 +/- 0.3 mg/dl) and 150 +/- 53 mumol/l (1.7 +/- 0.6 mg/dl)] in comparison with the group without rejection [97 +/- 18 mumol/l (1.1 +/- 0.2 mg/dl) and 115 +/- 35 mumol/l (1.3 +/- 0.4 mg/dl); p = NS]. On the other hand, the group with an early relapse of the first rejection and the group with two rejections were principally CR (62 and 60%, respectively), had partial remission with treatment (50 and 60%) and had worse renal function at 1 and 2 years [212 +/- 71 mumol/l (2.4 +/- 0.8 mg/dl) and 221 +/- 53 mumol/l (2.5 +/- 0.6 mg/dl)] than in the group with isolated KR (p < 0.05 and p < 0.001). In conclusion, despite intense immunosuppressive treatment, the frequency of rejection of a renal allograft in SKP is high. The response to treatment is satisfactory and does not affect the survival of the allograft in the short-term. However, multiple episodes or early relapse of rejection are associated with higher creatinine levels.