We investigated whether the risk of infection with malaria parasites was related to topography in the Usambara Mountains, Tanzania. Clinical surveys were carried out in seven villages, situated at altitudes from 300 m to 1650 m. Each village was mapped and incorporated into a Digital Terrain Model. Univariate analysis showed that the risk of splenomegaly declined with increasing altitude and with decreasing potential for water to accumulate. Logistic regression showed that altitude alone could correctly predict 73% of households where an occupant had an enlarged spleen or not. The inclusion of land where water is likely to accumulate within 400 m of each household increased the accuracy of the overall model slightly to 76%, but significantly improved predictions between 1000 m and 1200 m, where malaria is unstable, and likely to be epidemic. This novel approach illustrates how topography could help identify local areas prone to epidemics in the African highlands.