Following surgery for musculoskeletal infection, a positive suction drainage culture (SDC) is consistent with persistent sepsis. Our objective was to determine the effect of a negative SDC obtained in subsequent operations on the outcome of a musculoskeletal infection. 99 patients were prospectively enrolled, all treated surgically for musculoskeletal infection utilizing suction drainage and appropriate antimicrobial therapy. Surgery consisted of irrigation, debridement, and prosthetic exchange or implant removal. SDC was considered negative if all bottles resulted in negative cultures. Following SDC results, patients were placed into 1 of 2 treatment groups: 1) Negative SDC, and no new operation; or 2) Positive SDC, and new operation(s) until SDC was negative. Antibiotic therapy ranged from 6-12 weeks (osteomyelitis) to 10-21 d (soft tissue). Both groups were similar with regard to baseline characteristics. Cure was obtained in 91.8% of patients (56/61) in group 1 and 91.6% of patients (22/24) in group 2. Similar results were obtained in patients with an infection in the presence of an implant. In conclusion, a negative SDC following surgery for a musculoskeletal infection is a strong indication of eventual outcome.