OBJECTIVE. Enterovirus 71 has caused large epidemics of disease, resulting in many fatalities and severe sequelae, in Taiwan and some other countries. In this study, host genetic factors were investigated to link susceptibility to and clinical severity of enterovirus 71 infections. METHODS. We enrolled 219 enterovirus 71 case subjects and 97 control children. HLA typing was performed with sequence-specific primers, and polymorphisms of immune-related candidate genes were detected with polymerase chain reaction, followed by automated gene sequencing. RESULTS. Of the 219 enterovirus 71 cases, 26% (56 of 219 cases) were uncomplicated cases, 74% (163 of 219 cases) were complicated cases, 57% (125 of 219 cases) were complicated cases with central nervous system involvement, and 17% (38 of 219 cases) involved cardiopulmonary failure after central nervous system involvement. Univariate analyses showed that tumor necrosis factor α promoter type II (−308 A allele), HLA-A33, and HLA-DR17 were significantly associated with enterovirus 71 susceptibility. Multivariate analysis demonstrated that HLA-A33 was the gene most significantly susceptible to enterovirus 71. HLA-A2 was associated with the development of cardiopulmonary failure. CONCLUSIONS. HLA-A33, which is a common phenotype in Asian populations but is rare in white populations, was most significantly associated with enterovirus 71 infection, compared with the other candidate genes we studied, whereas HLA-A2 was significantly related to cardiopulmonary failure.