OBJECTIVES:  To compare economic and clinical outcomes between patients undergoing knee replacement with use of the DERMABOND® PRINEO® Skin Closure System vs. skin staples. METHODS:  Retrospective, observational study using the Premier Hospital Database. Patients (aged≥18 years) selected for study had an elective hospital admission, with discharge occurring between 1/1/2012-9/1/2015, carrying primary ICD-9-CM procedure and diagnosis codes for knee replacement and osteoarthritis (first qualifying=index admission). Patients were classified into two mutually-exclusive groups based on billing records during the index admission: those with billing record(s) for use of PRINEO (PRINEO group); those with billing record(s) for skin staples (staple group). Primary outcomes were index admission’s length of stay (LOS), total hospital costs, and discharge status (skilled nursing facility [SNF]/other vs. home/home health care); exploratory outcomes included operating room time (ORT) during index admission and 30, 60, and 90-day readmissions. The PRINEO and staple groups were propensity score matched (1:1/nearest neighbor/caliper=0.10) on patient, hospital, and provider characteristics. Multivariable regressions accounting for hospital-level clustering after matching were used to compare outcomes between study groups. RESULTS:  Each group comprised 971 patients (1,942 total patients; mean age=65.3y; % females=63.5%). The groups were generally well-balanced on matching covariates: mean standardized difference calculated across 49 covariates=0.049. Compared to the staple group, the PRINEO group had statistically significant: shorter LOS (2.8d vs. 3.2d, P=0.002), lower probability of discharge to SNF/other vs. home/home healthcare (26.4% vs. 38.5%, P=0.011), and lower probability of 30, 60, and 90-day readmissions (30-day, 1.8% vs. 4.4%, P=0.006; 60-day, 3.0% vs. 5.4%, P<0.001; 90-day, 5.4% vs. 7.4%, P=0.016). Differences between the groups for other outcomes were not statistically significant. CONCLUSIONS:  Among patients undergoing knee replacement in real world clinical practice, use of PRINEO vs. skin staples was associated with shorter LOS, less resource intensive discharge status, and lower probability of readmission.