BACKGROUND Enterovirus 71 (EV71) is causing life-threatening hand-foot-mouth disease in Asia. In Taiwan, EV71 epidemics with different predominant genotypes occurred in 1998 (C2), 2000-2001 (B4), and 2004-2005 (C4). This genotype replacement may have important implications for vaccine development and prediction of epidemics. A nationwide EV71 outbreak occurred again in 2008, which provided a unique opportunity to characterize clinical, virologic, and serologic features of this epidemic. METHODS We analyzed clinical and virologic data of 111 EV71 patients hospitalized in 2008 and prospectively conducted follow-ups of healthy children from June 2006 to December 2008. RESULTS Among the 111 EV71 inpatients, 21 (19%) developed complications. Among the 21 complicated cases, 15 had central nervous system complication only, 2 had acute heart failure, and 4 had central nervous system and pulmonary complications. In the prospective study, 11 symptomatic infections and 4 asymptomatic infections were detected. Twenty-two EV71 isolates were genotyped, and 21 of them belong to genotype B5, which is phylogenetically close to B5 viruses circulating in Southeast Asia. Serologic tests show that children infected with B5 viruses have lower geometric mean titers of neutralizing antibody against genotype C4 than those against genotype B5 (P = 0.004, t test). CONCLUSIONS The 2008 nationwide EV71 epidemic was caused by genotype B5 that was likely introduced to Taiwan from Southeast Asia. Clinical features of the 2008 epidemic were not different from those observed before in Taiwan. Potential antigenic variations between genotype C4 and B5 viruses could be detected and its long-term epidemiologic significance needs further investigation to clarify.