Daptomycin is an option for prosthetic joint infection (PJI) because it is bactericidal against gram-positive bacteria, including multiple-resistant isolates, and active against stationary-phase bacteria in biofilm present on implants. To evaluate its possible utility, we prospectively monitored 12 adults with gram-positive PJI who were not candidates for vancomycin. Pathogens included methicillin-resistant Staphylococcus aureus (n = 7), methicillin-resistant-coagulase-negative Staphylococci (n = 4), and methicillin-sensitive Staphylococcus aureus (n = 1). All patients completed a 6-week course of daptomycin 4 mg/kg/day. One died of an unrelated cause shortly after completing therapy. After a followup of 7 to 13 months, six patients had no clinical, laboratory, or radio-graphic signs of recurrence. One patient failed a first course and was subsequently treated with hardware removal and a second course with no recurrence. Five patients had culture-confirmed failure-all due to MRSA-including two during therapy despite hardware removal and three 1 to 10 months after completing daptomycin but with retained hardware. The efficacy of daptomycin 4 mg/kg/day is uncertain in patients with PJI, especially when hardware is retained. Further study is needed to determine why in vitro data did not predict clinical success and to ascertain any potential benefit from higher doses.