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We conducted a clinical trial of oral valganciclovir, a drug with in vitro activity against Kaposi sarcoma (KS)–associated herpesvirus (KSHV), in classic KS. Five human immunodeficiency virus–seronegative participants received valganciclovir for up to six 4-week cycles at doses used for cytomegalovirus infection. None of the study subjects showed an objective response; KS progressed in 4 subjects after 1–4 cycles and remained stable in 1 subject after 6 cycles. KS biopsies showed minimal lytic KSHV antigen and gene expression at baseline and no treatment-associated changes. Although valganciclovir was not active against KS in this setting, other appropriately targeted anti-herpesviral strategies may prove to be more effective.