BACKGROUND & OBJECTIVES: Scrub typhus is a major public health threat in South and Southeastern Asian countries including India. Understanding local patterns of disease and factors that place individuals at risk is pivotal to future preventive measures against scrub typhus. The primary aim of this study was to identify specific epidemiological and geographical factors associated with an increased risk of developing scrub typhus in this region. METHODS: We mapped 709 patients from Tamil Nadu, Andhra Pradesh and Telangana who were admitted to the Christian Medical College (CMC) Hospital, Vellore, Tamil Nadu, India, for the period 2006-2011, assessed seasonality using monthly counts of scrub typhus cases, and conducted a case-control study among a subset of patients residing in Vellore. RESULTS: The geographic distribution of cases at CMC Hospital clusters around the Tamil Nadu-Andhra Pradesh border. However, distinct hotspots clearly exist distal to this area, near Madurai and the coast in Tamil Nadu, and in the Northeast of Andhra Pradesh. Seasonally, the highest numbers of cases were observed in the cooler months of the year, i.e. September to January. In the case-control analysis, cases were more likely to be agricultural laborers (OR 1.79, 95% CI 1.01 - 3.15), not wear a shirt at home (OR 4.23, 95% CI 1.12 - 16.3), live in houses adjacent to bushes or shrubs (OR 1.95, 95% CI 1.08 - 3.53), and live in a single room home (OR 1.75, 95% CI 1.02 - 3.01). On binary logistic regression, the first three of these variables were statistically significant. INTERPRETATION & CONCLUSIONS: With the growing number of cases detected in India, scrub typhus is fast emerging as a public health threat and further research to protect the population from this deadly infection is essential. Health education campaigns focusing on the agricultural workers of Southern India, especially during the cooler months of the year, can serve as an important public health measure to control infection.