Endemic Burkitt's lymphoma (eBL), the most common childhood cancer in sub-Saharan Africa, occurs at a high incidence in western Kenya, a region that also experiences holoendemic malaria. Holoendemic malaria has been identified as a co-factor in the etiology of this cancer. We hypothesized that eBL may cluster spatially within this region. Medical records for all eBL cases diagnosed from 1999 through 2004 at Nyanza Provincial General Hospital were reviewed for case residential information to examine this hypothesis. Two cluster detection methods, Anselin's Local Moran test for spatial autocorrelation and a spatial scan test statistic, were applied to this residential data to determine whether statistically significant high- and low-risk areas were present in the Province. During the 6-year study period, 272 children were diagnosed with eBL, with an average annual incidence of 2.15 cases per 100,000 children. Using Empirical Bayes smoothed rates, the Local Moran test identified 1 large multi-centered area of low eBL risk (p-values < 0.01) and 2 significant multi-centered clusters of high eBL risk (p-values < 0.001). The spatial scan detected 3 small independent low-risk areas (p-values < 0.02) and 2 high-risk clusters (p-values = 0.001), both similar in location to those identified from the Local Moran analysis. Significant spatial clustering of elevated eBL risk in high-malaria transmission regions and of reduced incidence where malaria is infrequent suggests that malaria plays a role in the complex eBL etiology, but that additional factors are also likely involved. © 2006 Wiley-Liss, Inc.