Late-onset cytomegalovirus (CMV) disease remains common in CMV serology naïve kidney transplant patients of CMV serology positive organs (D+/R–) despite the use of antiviral prophylaxis. We studied clinical efficacy of 6-month low-dose valganciclovir (VGCV) prophylaxis, risk factors for late-onset CMV disease and its impact on kidney transplant outcomes. Between October 2005 and December 2009, 166 consecutive D+/R– kidney alone and simultaneous pancreas and kidney transplant patients received VGCV 450 mg daily for 6 months after transplantation. After a median follow-up of 3.2 years, 30 cases of CMV disease occurred within the first 2 years after transplantation with a cumulative incidence of 11.5 and 18.1% at 1 and 2 years, respectively. The use of an induction agent with rabbit antithymocyte globulin and older donor age were factors associated with the risk of late-onset CMV disease (AHR 2.91, 95% CI 1.18–7.20, p = 0.021 and AHR 1.03, 95% CI 1.01–1.06, p = 0.016, respectively). Late-onset CMV disease was associated with increased risk for death-uncensored graft loss (AHR 2.95, 95% CI 1.15–7.61, p = 0.025). In conclusion, late-onset CMV disease continues to negatively impact kidney transplant outcome despite 6-month low-dose VGCV prophylaxis. Investigations focusing on novel preventive approaches should be emphasized.