Seroprevalence data suggest that West Nile virus activity in southern Romania dates to the 1960s or earlier. In the summer of 1996, southeastern Romania and especially Bucharest experienced an unprecedented epidemic of West Nile encephalitis/meningitis, with at least 393 hospitalized cases and 17 deaths. Contributing factors included a susceptible avian population and urban/suburban infrastructural conditions that favored the production of large numbers of Culex pipiens pipiens. The epidemic ended spontaneously in early autumn. Results of serosurveys conducted as the epidemic waned pointed to the recent, novel introduction of West Nile virus to Bucharest. During 1997-2000, 39 scattered human cases of clinical West Nile virus infection (mean, 10 per year; range, 5-14 per year)--including 5 (13%) fatal cases--were diagnosed serologically throughout the region, but epidemic disease did not recur. Results of limited ecologic surveillance efforts during 1997-2000 suggested the existence of numerous focal areas of enzootic West Nile virus activity within the region. The authors explore the possible factors that led to the 1996 epidemic, review the ecologic and human data gathered during the postepidemic period of 1997-2000, summarize the public health lessons offered by the epidemic and its aftermath, and speculate on the future of epidemic West Nile virus activity in southeastern Romania.