BACKGROUND: A randomized, double-blind study was conducted to evaluate the pharmacokinetics of ganciclovir following oral administration of ganciclovir or valganciclovir for prophylaxis of cytomegalovirus (CMV) disease in solid organ transplant recipients (n = 240/372). METHODS: The correlations between individual exposure to ganciclovir during prophylaxis, with CMV viremia incidence during and after treatment, CMV disease up to 12 months posttransplant, and hematological toxicity were assessed. RESULTS: Mean daily areas under the curve (AUCs) of ganciclovir from valganciclovir and oral ganciclovir were 46.3 +/- 15.2 and 28.0 +/- 10.9 microg.h/ml (mean +/- SD), respectively. Viremia was suppressed during prophylaxis when exposure to ganciclovir was 40-50 microg.h/ml, AUCs typical of those achieved in valganciclovir-treated patients. The development of viremia 1 month after ending prophylaxis was also reduced with higher ganciclovir AUC (median predicted incidence, 20% and 10% at AUCs of 33 and 50 microg h/ml, respectively). The development of CMV disease within 1 year of transplant was 17.6% and independent of prophylactic exposure to ganciclovir. There was only a weak tendency to increased neutropenia and leukopenia with higher ganciclovir exposure. CONCLUSIONS: The greater systemic exposure to ganciclovir delivered by valganciclovir was associated with delayed development of viremia. There was only a weak association between AUC and hematological toxicity.