Thirteen episodes of Staphylococcus epidermidis sepsis occurred over a 20-month period in 11 patients receiving general surgical and medical care. These episodes were characterized by fever, toxicity, multiple positive blood cultures, and uniformly colonized intravascular catheters. An additional 16 patients had possible sepsis. Four associated deaths occurred; all three patients autopsied had multiple pulmonary abscesses in which gram-positive cocci were profusely present. In individual patients, prolonged episodes of septicemia were confirmed by multiple blood culture isolates of S. epidermidis, identical in antibiotic resistance pattern, phage type, and biotype. A prominent feature of the S. epidermidis isolates was resistance to many commonly used antimicrobial agents. Case-control studies and review of laboratory records indicated a significant association between multiply resistant S. epidermidis blood isolates and prolonged hospitalization and parenteral hyperalimentation. Most of these patients were hospitalized in the intensive care unit; nose and hand cultures taken from the personnel showed frequent carriage of multiply resistant S. epidermidis Staphylococcus epidermidis associated with intravascular devices may produce life-threatening bloodstream infections.