The specific risk factors for surgical site infection (SSI) in orthopaedic oncology patients undergoing endoprosthetic reconstruction have not previously been evaluated in a large prospective cohort. The current study aims to define patient and procedure-specific risk factors for SSI in patients undergoing surgical excision and endoprosthetic reconstruction of the lower extremity for oncologic indications using the prospectively collected data of the Prophylactic Antibiotic Regimens in Tumor Surgery (PARITY) trial. PARITY was a multicenter, blinded, parallel two-arm design randomized controlled trial that aimed to determine the effect of long (5 days) vs. short duration (24 hours) postoperative prophylactic antibiotics on the rate of SSI in patients undergoing surgical excision of the femur or tibia. The primary analysis of the PARITY study of 604 eligible patients was published in the Journal of the American Medical Association (Oncology) on January 6, 2022. In this secondary analysis of the PARITY data, a multivariate Cox proportional hazards regression model was constructed to explore predictors of SSI within one year postoperatively. Based on the outcomes of the univariate analysis and theoretical relationships, the following variables were selected for inclusion in the regression model: age, sex, tumor location (femur vs. tibia) and type (primary bone vs. soft tissue sarcoma invading bone vs. oligometastatic bone disease), soft tissue mass, preoperative neutropenia, neoadjuvant chemotherapy, operative time, total muscle excised, intraoperative vancomycin powder use, silver coated prosthesis, prosthesis betadine soak, arthroplasty helmet use, operative laminar flow, postoperative suction drain, urinary catheter, postoperative negative pressure wound therapy, hospital length of stay (LOS) and adjuvant chemotherapy. The results of the model are presented with hazards ratios (HR) and 95% confidence intervals (CI). A total of 96 of 604 patients (15.9%) experienced an SSI. Of the 22 variables analysed in the univariate analysis, four variables achieved statistical significance: tumor type, operative time, volume of muscle excised and hospital LOS. However, only hospital LOS was found to be independently predictive of SSI in the multivariate regression analysis (HR = 1.03, 95% CI = [1.01–1.05], P = 0.001). An omnibus test of model coefficients demonstrated that the model showed significant improvement over the null model (χ2 = 76.6, P 0.7 as a cut off for exclusion. This secondary analysis of the PARITY study data found that among the potential risk factors for SSI following endoprosthetic reconstruction of the lower extremity, the only independent risk factor on multivariate analysis was hospital LOS. It therefore may be reasonable for clinicians to consider streamlined discharge plans for orthopaedic oncology patients to potentially reduce the risk for SSI.