Context There are concerns that malaria control measures such as use of insecticide treated bed nets, by delaying acquisition of immunity, might result in an increase in the more severe manifestations of malaria. An understanding of the relationships among the level of exposure to Plasmodium falciparum, age, and severity of malaria can provide evidence of whether this is likely. Objective To describe the clinical manifestations and case fatality of severe P falciparum malaria at varying altitudes resulting in varying levels of transmission. Design, Setting, and Patients A total of 1984 patients admitted for severe malaria to 10 hospitals serving populations living at levels of transmission varying from very low (altitude_1200 m) to very high (altitude_600 m) in a defined area of northeastern Tanzania, studied prospectively from February 2002 to February 2003. Data were analyzed in a logistic regression model and adjusted for potential clustering within hospitals. Main Outcome Measures Specific syndromes of severe malaria; mortality. Results The median age of patients was 1 year in high transmission, 3 years in moderatetransmission, and 5 years in low transmission areas. The odds of severe malarialanemia (hemoglobin _5 g/dL) peaked at 1 year of age at high transmission and at 2 years at moderate and low transmission intensities and then decreased with increasing age (P=.002). Odds were highest in infants (0-1 year: referent; 2-4 years: odds ratio [OR], 0.83; 95% confidence interval [CI], 0.72-0.96), 5 to _15 years: OR, 0.44; 95% CI, 0.27-0.72;_15 years: OR, 0.44; 95% CI, 0.27-0.73; P_.001) and high transmission intensity areas (altitude _600 m: referent; 600 m to 1200 m: OR, 0.55; 95% CI, 0.35-0.84; _1200 m: OR, 0.55; 95% CI, 0.26-1.15; P for trend=.03). The odds of cerebral malaria were significantly higher in low transmission intensity areas (altitude of residence _600 m: referent; 600 m to 1200 m: OR, 3.17; 95% CI, 1.32-7.60; _1200 m: OR, 3.76; 95% CI, 1.96-7.18; P for trend=.003) and with age 5 years and older (0-1 year: referent; 2-4 years: OR, 1.57; 95% CI, 0.82-2.99; 5 to _15 years: OR, 6.07; 95% CI, 2.98-12.38; _15 years: OR, 6.24; 95% CI, 3.47-11.21; P_.001). The overall case-fatality rate of 7% (139 deaths) was similar at high and moderate levels of transmission but increased to 13% in low transmission areas (P=.03), an increase explained by the increase in the proportion of cases with cerebral malaria. Conclusions Age and level of exposure independently influence the clinical presentation of severe malaria. Our study suggests that an increase in the proportion of cases with more fatal manifestations of severe malaria is likely to occur only after transmission has been reduced to low levels where the overall incidence is likely to be low.