Background: Sporadic Creutzfeldt-Jakob disease (CJD) is a rare neurodegenerative disease caused by prions that is randomly distributed in all countries, with an overall yearly mortality rate of about 1–2 cases per million people. On a few occasions, however, sporadic CJD occurred with higher than expected rates, but further investigations failed to recognize any convincing causal link. In Italy, cluster analyses of sporadic CJD cases have not been performed previously. Objective: To investigate the geographical distribution of sporadic CJD using municipality geographical data of Apulia with the aim of detecting spatial clusters of disease. Patients and Methods: Patients included in this study were diagnosed as probable or definite sporadic CJD and were residents of the Apulia Region (Italy). Bayesian hierarchical models with spatially structured and unstructured random components were used to describe the spatial pattern of the disease and to assess the extent of heterogeneity among municipalities. The Kulldorff-Nagarwalla scan test and the flexible spatial scan statistic were used for detecting spatial clusters. Results: Smoothed Bayesian relative risks above the null value were observed in a few adjacent municipalities in the north and middle areas of Apulia. However, both the circular scanning method and the flexible spatial scan statistic identified only a single cluster in the central part of the region. Conclusion: Geographical analyses and tests for spatial randomness identified a restricted area with an unusually high number of sporadic CJD cases in the Apulia region of Italy. Environmental and genetic risk factors other than mutations in the prion protein gene however, need to be investigated.