BACKGROUND: Immunosuppressive and antiviral prophylactic drugs are needed to prevent acute rejection and infection after transplantation. We assessed the efficacy and safety of the introduction of universal valganciclovir prophylaxis in combination with a tacrolimus/mycophenolate-based regimen in kidney transplantation at our centre. METHODS: We reviewed all consecutive patients who underwent kidney transplantation over a 5.5-year period. Patients transplanted from January 2000 to March 2003 (period 1) were compared to patients from April 2003 to July 2005 (period 2). In period 1 patients were treated with basiliximab, cyclosporine, steroids and mycophenolate (or azathioprine). Prophylaxis with valacyclovir was prescribed in cytomegalovirus (CMV) D+/R- patients, while any R+ patients were managed with a preemptive approach. In period 2, immunosuppression consisted of basiliximab or thymoglobulin induction, tacrolimus, steroids and mycophenolate. Three-month CMV prophylaxis with valganciclovir was used in all at-risk patients. RESULTS: Data analysis included 73 patients (period 1) and 70 (period 2). Acute rejection was more frequent in period 1 than in period 2 (42% vs 7%, p <0.001). Overall, 30% of patients in period 1 were diagnosed with CMV infection/disease requiring antiviral treatment, compared with 11.4% in period 2 (p = 0.003). Late-onset CMV disease remained a problem in D+/R- patients in both periods. There was no difference in incidence of BK virus nephropathy, fungal infections, PTLD, graft loss or mortality. However, 4 cases (5.7%) of delayed transient asymptomatic agranulocytosis were observed in period 2. CONCLUSIONS: The present analysis indicates that the combined regimen introduced in period 2 improved clinical results with a significant decrease in acute rejection and in CMV infection/disease incidence. However, a unique syndrome of delayed transient agranulocytosis probably due to drug myelotoxicity was observed in a subset of patients.