Hypotheses: Surgical patients with antibiotic-resistant gram-positive coccal (GPC) infections have a poorer prognosis than those with antibiotic- sensitive GPC infections, and colonization with resistant GPC predisposes to the development of resistant GPC infections. Design: All infections among surgical patients from December 1, 1996, to December 1, 1998, were followed up prospectively. Patients with antibiotic-sensitive and antibiotic-resistant GPC infections were compared. Cohorts were also subdivided on the basis of GPC species, colonization status, and immunosuppression. Setting: The surgical wards and intensive care units of a tertiary care, university hospital. Main Outcome Measures: In-hospital mortality, in-hospital mortality during antibiotic therapy, length of stay, and length of stay from the time of initiation of antibiotics to discharge. Results: Antibiotic-resistant GPC infection compared with antibiotic-sensitive GPC infection was associated with a higher mortality and previous colonization rate (25.8% and 31.0% vs 17.6% and 8.8%, respectively; P = .04 and P<.001, respectively) and a markedly longer length of stay (55.0 ± 3.3 vs 31.0 ± 2.0 days; P<.001). Length of stay and treatment to discharge times were longer after resistant Staphylococcus aureus infections than after resistant Staphylococcus epidermidis infections. The mortality and length of stay of patients with gentamicin-resistant or vancomycin-resistant enterococcal infections were equivalently higher than those with antibiotic-sensitive enterococcal infections. Transplant recipients with resistant enterococcal infection had the highest mortality (41.9%). Conclusions: Surgical patients who develop antibiotic-resistant GPC infections have a significantly higher mortality rate, longer length of stay, and longer treatment to discharge time than patients with antibiotic-sensitive GPC infections. Colonization with resistant GPC predisposes to resistant GPC infection Gentamicin-resistant enterococcus appears to be as virulent as vancomycin-resistant enterococcus.