Comparative data are needed to define the use of agents to treat serious gram-positive cocci infections. This prospective, open-label, observational cohort study included adults receiving daptomycin, linezolid, vancomycin, or oxacillin/cefazolin for complicated skin and skin structure infections, bacteremia, endocarditis, or osteomyelitis. Primary outcome was clinical response at 180 days. Secondary outcomes included response at the end of therapy, antibiotic switch due to failure, length of stay (LOS), LOS after antibiotic start, mortality, infection-related readmission, and antibiotic and hospitalization costs. One hundred seventeen patients were evaluated for complicated skin and skin structure infections (n= 37), bacteremia (n = 49), endocarditis (n = 10), and osteomyelitis (n = 21). Daptomycin (P = 0.008) and linezolid (P = 0.02) were used more often as second-line therapy. No significant differences were found in outcomes except LOS (P = 0.05), and hospitalization costs (P = 0.004) were higher with linezolid; antibiotic costs were higher for linezolid (P = 0.001) and daptomycin (P = 0.03). Response rates were similar for the study drugs, although daptomycin and linezolid were used as second-line therapy and associated with higher drug costs.