The changing microbiology of bacteremia among narcotic addicts in Detroit raised concerns about current presumptive antimicrobial therapy. In a one-year study of incidence, microbiology, sites, and risk factors, 180 bacteremic addicts (15% of addict-related admissions) were followed prospectively. Cases of bacteremia were caused by methicillin-sensitive Staphylococcus aureus (33%), methicillin-resistant S. aureus (MRSA, 24%), streptococci (20%), mixed organisms (11%), Pseudomonas aeruginosa (9%), and miscellaneous other single organisms (3%). Endocarditis (41%) and abscess or cellulitis (34%) were usually found. Multivariate analysis of host factors and addiction habits yielded results predictive of bacterial species but not of infection sites. Previous hospitalization, long-term addiction, and nonprescribed antibiotic use were associated with MRSA acquisition (odds ratio, 8.6:1). All addicts with polymicrobial or P. aeruginosa bacteremia abused pentazocine and tripelennamine (P = .05). Many of the addicts with streptococcal bacteremia were women who did not abuse antibiotics (odds ratio, 20.7:1). Physicians inappropriately prescribed empiric antibiotics for 67 of 72 addicts with MRSA, P. aeruginosa, or polymicrobial infection. The results of regression analysis suggest that, guided by the patient's history, the physician can prescribe appropriate empiric antimicrobial therapy for bacteremia in the febrile addict in Detroit.