Background: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are associated with increased red blood cell transfusion (RBT) demand. Although the deleterious effects of RBT are documented in various settings, its effect in this setting is obscure. In this study, we evaluated the effects of different-grade RBT on the short- and long-term outcomes of CRS and HIPEC. Methods: We analyzed 231 patients with diffuse malignant peritoneal mesothelioma (DMPM) and 273 patients with pseudomyxoma peritonei (PMP) operated in our unit. RBT was categorized according to the amount of packed red blood cell units (PRBCs) administered (0, 1–2, 3–5, > 6). The effects of RBT on long-term oncological outcomes [progression-free survival (PFS) and overall survival (OS)] were assessed by using multivariate analysis. Results: Overall, 74% of the patients were transfused with a median of 2 PRBCs (range 0–37). Transfusion level correlated with operative time, surgical extent (as measured by the peritoneal carcinomatosis index), and age. Postoperatively, patients with major transfusion (> 6 PRBCs) had increased mortality rate (11.1%, p = 0.01) and length of hospital stay (31.2 ± 16.8 days, p = 0.01) compared with other levels of RBT. RBT was dose-dependently associated with oncological outcomes in both DMPM and PMP for both PFS [hazard ratio (HR) = 1.40, 95% confidence interval (CI) 1.12–1.74, p = 0.003; HR = 1.44, 95% CI 1.15–1.81, p = 0.001, respectively] and OS (HR = 1.57, 95% CI 1.21–2.03, p = 0.001; HR = 1.43, 95% CI 1.15–1.90, p = 0.01, respectively). Conclusions: Our data show a dose-dependent relationship between RBT and oncological outcomes. Further research to develop transfusion sparing protocols is needed in this extensive surgical procedure.