Three outbreaks of Corynebacterium diphtheriae infection occurred in Seattle's Skid Road from 1972 through 1982. The first involved a single toxigenic, intermedius biotype clone, whereas the second and third outbreaks involved nontoxigenic mitis and gravis strains. Of 1100 total infections, 947 (86%) were cutaneous. The incidence was highest in winter and spring. In Skid Road, the estimated attack rate during 17 months in 1974 to 1975 was 5% for whites and 27% for native Americans. Streptococcus pyogenes was isolated from 73% of diphtheritic and 41% of nondiphtheritic skin lesions (P less than 0.001). Skin infection and environmental contamination by C. diphtheriae were correlated. Complications occurred in 21% of symptomatic nasopharyngeal and 3% of cutaneous toxigenic intermedius infections (P less than 0.001), and were significantly correlated with ages 60 years or more. Preferential use of erythromycin for diphtheria and pyodermas preceded plasmid-mediated resistance to erythromycin in C. diphtheriae. Diphtheria outbreaks in urban alcoholic persons are associated with poor hygiene, crowding, season, contaminated fomites, underlying skin disease, hyperendemic streptococcal pyoderma, and introduction of new strains from exogenous reservoirs.