Oncologic resection and endoprosthetic reconstruction of lower-extremity musculoskeletal tumors are complex procedures fraught with multiple modes of failure. A robust assessment of factors contributing to early reoperation in this population has not been performed in a large prospective cohort. The aim of the present study was to assess risk factors for early reoperation in patients who underwent tumor excision and endoprosthetic reconstruction, with use of data from the Prophylactic Antibiotic Regimens in Tumor Surgery (PARITY) trial. Baseline characteristics were assessed, including age, sex, tumor type, tumor location, presence of a soft-tissue mass, diabetes, smoking status, chemotherapy use, and neutropenia. Operative factors were recorded, including operative time, topical antibiotics, silver-coated prosthetics, endoprosthetic fixation, extra-articular resection, length of bone resected, margins, tranexamic acid, postoperative antibiotics, negative-pressure wound therapy, and length of stay. Univariate analysis was utilized to explore the differences between patients who did and did not undergo reoperation within 1 year postoperatively, and a multivariate Cox proportional hazards regression model was utilized to explore the predictors of reoperation within 1 year. A total of 155 (25.7%) of 604 patients underwent ≥1 reoperation. In univariate analysis, tumor type (p < 0.001), presence of a soft-tissue mass (p = 0.045), operative time (p < 0.001), use of negative-pressure wound therapy (p = 0.010), and hospital length of stay (p < 0.001) were all significantly associated with reoperation. On multivariate assessment, tumor type (benign aggressive bone tumor versus primary bone malignancy; hazard ratio [HR], 0.15; 95% confidence interval [CI], 0.04 to 0.63; p = 0.01), operative time (HR per hour, 1.15; 95% CI, 1.10 to 1.23; p < 0.001), and use of negative-pressure wound therapy (HR, 1.93; 95% CI, 1.30 to 2.90; p = 0.002) remained significant predictors of reoperation within 1 year. Independent variables associated with reoperation within 1 year in patients who underwent tumor resection and endoprosthetic reconstruction included tumor type (benign aggressive bone tumor versus primary bone malignancy), operative time, and use of negative-pressure wound therapy. These results will help to inform patients and surgeons regarding the risk of reoperation by diagnosis and reinforce operative time as a factor influencing reoperation. These results also support further investigation into the use of negative-pressure wound therapy at the time of surgery in this patient population. Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.