In urban environments, raccoons (Procyon lotor) may act as reservoirs for an array of pathogenic organisms, presenting spillover risks for human, domestic animal, and captive (zoo) animal populations. Over 5 yr, 159 raccoons from a high-density raccoon population in St. Louis, Missouri (USA), were surveyed for exposure to canine distemper virus (CDV), canine adenovirus 1 (CAV-1); feline parvovirus (FPV; =feline panleukopenia), and several serovars of Leptospira interrogans. Exposure to each of the viruses and two Leptospira serovars (grippotyphosa and icterohemorrhagiae) was detected (prevalence of CDV = 54.1%; FPV = 49.7%; CAV-1 = 6.9%; L. interrogans icterohemorrhagiae = 8.9%; L. interrogans grippotyphosa = 6.3%). Eighty percent of raccoons showed evidence of exposure to at least one of the five primary pathogens, and 39% were positive for multiple species. Among the viruses, there was a significant co-occurrence of CDV and CAV-1. Longitudinal data on a subset of animals revealed that among individuals who were diagnosed as seropositive on first capture, 33–100% became seronegative for the pathogen of interest when reexamined at a later date. Thus, free-ranging urban raccoons have been exposed to multiple infectious agents, some of which may pose risks to humans and to nonvaccinated domestic and captive animal populations.