Thrombotic microangiopathy (TMA) is rare after transplantation and is associated with a high incidence of kidney graft dysfunction. Between December 2000 and March 2006, 136 simultaneous pancreas–kidney transplantations were performed with an incidence of TMA of 5.1% (71.4% localized to kidney allograft). All cases were diagnosed during the first three months and were attributed to tacrolimus; 74% were women. Systemic TMA presented higher values of lactate dehydrogenase (2658 ± 659 U/L vs. 1331 ± 473 U/L, p = 0.04) and a greater decrease in hematocrit (45.8 ± 17.7% vs. 19.2 ± 6%, p = 0.02) than in localized TMA. Acute kidney rejection complicated almost 90% of the cases with 43% of kidney graft lost. Tacrolimus was switched to sirolimus and fresh-frozen plasma was administered. Creatinine clearance after a mean follow-up of two yr was 100.7 mL/min/1.73 m2 and 57.9 mL/min/1.73 m2 in patients with systemic and localized TMA, respectively. In conclusion, sirolimus is an alternative to TMA associated with tacrolimus.