To measure the impact of orthopedic surgical-site infections (SSIs) on quality of life, length of hospitalization, and cost. A pairwise-matched (1:1) case-control study within a cohort. A tertiary-care university medical center and a community hospital. Cases of orthopedic SSIs were prospectively identified by infection control professionals. Matched controls were selected from the entire cohort of patients undergoing orthopedic surgery who did not have an SSI. Matching variables included type of surgical procedure, National Nosocomial Infections Surveillance risk index, age, date of surgery, and surgeon. Quality of life, duration of postoperative hospital stay, frequency of hospital readmission, overall direct medical costs, and mortality rate. Fifty-nine SSIs were identified. Each orthopedic SSI accounted for a median of 1 extra day of stay during the initial hospitalization (P = .001) and a median of 14 extra days of hospitalization during the follow-up period (P = .0001). Patients with SSI required more rehospitalizations (median, 2 vs 1; P = .0001) and more total surgical procedures (median, 2 vs 1; P = .0001). The median total direct cost of hospitalizations per infected patient was $24,344, compared with $6,636 per uninfected patient (P = .0001). Mortality rates were similar for cases and controls. Quality of life was adversely affected for patients with SSI. The largest decrements in scores on the Medical Outcome Study Short Form 36 questionnaire were seen in the physical functioning and role-physical domains. Orthopedic SSIs prolong total hospital stays by a median of 2 weeks per patient, approximately double rehospitalization rates, and increase healthcare costs by more than 300%. Moreover, patients with orthopedic SSIs have substantially greater physical limitations and significant reductions in their health-related quality of life.