This study investigated the incidence of severe disease following primary exposure to Plasmodium falciparum by nonimmune children and adults in Irian Jaya, Indonesia. Four months after arrival, the cross-sectional prevalence of P. falciparum was 72%, and the monthly cumulative incidence of clinical diagnoses of malaria was 81%. Delirium or unconsciousness prompted evacuation to the hospital. Records of emergency evacuation of persons with a clinical diagnosis of malaria revealed an incidence density among adults (>15 years) of 1.34 events/person-year in the third month, whereas the rate in children remained stable at approximately 0.25 events/person-year (relative risk = 4.51, 95% confidence interval [CI] = 1.94-11). Through the first 6 months of exposure, 23.2% of adults were evacuated to the hospital with a diagnosis of malaria compared with 8.6% of children (relative risk = 2.7, 95% CI = 1.9-3.8). In this population with relatively few infants or people of advanced age, the risk of severe disease following primary exposure to P. falciparum increased with age.