Homeless people are particularly exposed to ectoparasites, but their exposure to arthropod-borne diseases has not been evaluated systematically. A medical team of 27 persons (7 nurses, 6 infectious disease residents or fellows, 2 dermatologists, and 12 infectious disease specialists) visited the 2 shelters in Marseilles, France, for 4 consecutive years. Homeless volunteers were interviewed, examined, and received care; and blood was sampled for cell counts and detection of bacteremia, antibodies to louse-borne (Rickettsia prowazekii, Bartonella quintana, and Borrelia recurrentis), flea-borne (R. typhi, R. felis), mite-borne (R. akari), and tick-borne (R. conorii) bacterial agents. We selected sex- and age-adjusted controls among healthy blood donors. Over 4 years, 930 homeless people were enrolled. Lice were found in 22% and were associated with hypereosinophilia (odds ratio, 5.7; 95% confidence intervals, 1.46-22.15). Twenty-seven patients (3%) with scabies were treated with ivermectin. Bartonella quintana was isolated from blood culture in 50 patients (5.3%), 36 of whom were treated effectively. The number of bacteremic patient increased from 3.4% to 8.4% (p = 0.02) over the 4 years of the study. We detected a higher seroprevalence to Borrelia recurrentis, R. conorii, and R. prowazekii antibodies in the homeless. Our study shows a high prevalence of louse-borne infections in the homeless and a high degree of exposure to tick-borne diseases and scabies. Despite effective treatment for Bartonella quintana bacteremia and the efforts made to delouse this population, Bartonella quintana remains endemic, and we found hallmarks of epidemic typhus and relapsing fever. The uncontrolled louse infestation of this population should alert the community to the possibility of severe re-emerging louse-borne infections.