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There are rare comparative studies of the clinical and laboratory features of severe and moderate malaria, including predictors of poor outcome, in rural and urban areas for regions of high malaria transmission. We therefore studied 2,235 children hospitalized for malaria in a rural (Lambaréné) and an urban (Libreville) area in Gabon between January 2001 and December 2002. From children screened, 33% and 48% were hospitalized for malaria in Libreville and Lambaréné, respectively (P < 0.001). Two malaria clinical groups were identified according to the World Health Organization 2000 classification of severe malaria. In both areas, severe malaria was characterized by a high proportion of severe anemia. The case fatality rate was 5-fold lower in Lambaréné than in Libreville (1% versus 5%; P < 0.0001). In both sites, cerebral malaria associated with respiratory distress was the most important predictor of fatal malaria (odds ratio = 10.7, 95% confidence interval = 4.8–23.8 P < 0.0001).