High engraftment rates are critical to any patient-derived xenograft (PDX) program and the loss of PDX models due to the development of lymphoproliferative tumors (LTs) is costly and inefficient. We hypothesized that routine injection of rituximab, an anti-CD20 antibody, at the time of implantation would reduce the incidence of LTs. Rituximab injection was added to the standard PDX engraftment protocol. Univariate analysis and multivariate logistic regression were used to determine the significance of various factors. A total of 811 generations of PDX were implanted with 406 receiving rituximab with implantation. On multivariable analysis, rituximab was an independent factor for decreased LT formation across the entire cohort (OR 0.465, 95% CI 0.271-0.797, p = 0.005). Hepatocellular carcinomas (OR 0.319, 95% CI 0.107-0.949, p = 0.040) and cholangiocarcinomas (OR 0.185, 95% CI 0.049-0.696, p = 0.113) were the specific malignant histologic subtypes that demonstrated the greatest benefit. The frequency of LTs decreased across the entire cohort with rituximab administration and PDX tumors that are traditionally associated with higher rates of LT formation, HCCs and CCAs, appear to benefit the most from rituximab treatment. Routine use of rituximab at the time of tumor implantation may have significant programmatic benefits for laboratories that utilize PDX models.