Background Cytomegalovirus (CMV) is the most common opportunistic infection after solid-organ transplant. Valganciclovir prophylaxis significantly reduces disease, but limited data are available on its use in children. Recently, an increase in delayed-onset CMV disease has been noted with some arguing that longer prophylaxis may decrease late-onset disease. Methods Single-center, retrospective analysis of pediatric renal transplant patients receiving 24 weeks valganciclovir prophylaxis (15 mg/kg/day, maximum 900 mg/day) from January 2004 to December 2008, aiming to measure the incidence of CMV disease and toxicity of valganciclovir. Results We enrolled 111 patients, 60% males, 46% African Americans, and median age at transplant 14.5 years (range 1.4–20.4 years). Sixty-nine percent of donors and 44% of recipients were seropositive pretransplant. Median duration of valganciclovir use was 5.9 months (range 0.5–24 months). CMV viremia and disease occurred in 27% and 4.5%, respectively. All patients with disease presented after prophylaxis ended and all were D+/R−. Thymoglobulin use (P=0.04) and positive donor CMV status (P=0.02) were associated with a higher risk of CMV viremia. Twenty-four percent had hematologic toxicity directly associated with valganciclovir. Conclusions Valganciclovir use in children was effective as prophylaxis against CMV disease; no children at our institution developed disease while on therapy. Our regimen of 24 weeks of prophylaxis was associated with a lower rate of late-onset disease than previous reports with 12-week regimens. Further controlled studies should be considered to compare longer versus shorter periods of prophylaxis and dose reductions and their impact on prevention of late-onset disease, resistance, cost, and toxicity.