Background: The use of hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer (CRC) with peritoneal carcinomatosis (PC) is still very controversial. The National Comprehensive Cancer Network guideline only recommends cytoreductive surgery (CRS) combined with HIPEC for colon cancer with PC for patients with limited metastases and can be removed with surgery. The short-term and long-term outcomes between colon versus rectal origin in this setting remain unclear. The present study compared our experience in the management of colon versus rectal cancer with PC through CRS-HIPEC and investigated whether the feasibility of extending the indication to the PC of rectal origin. Materials and Methods: The data of 78 and 10 patients with PC of colon and rectal origin, respectively, were collected from a prospectively maintained database of patients receiving CRS-HIPEC for peritoneal surface malignancy at any period during 2002–2018. CRS followed by HIPEC with mitomycin-C or 5-fluorouracil plus oxaliplatin was administered at 42° for 60 min. In addition, adjuvant chemotherapy was administered postoperatively. Data on sex, age, prior surgical score, preoperative or postoperative peritoneal cancer index (PCI), completeness of cytoreduction (CC) score, blood loss, operation time, transfusion unit, and hospital stay were recorded. Survival was compared between the colon and rectal groups. Results: The average patient was 56.4 years old, and 44 were men and 44 were women. The mean preoperative and postoperative PCI scores were 15.6 and 6.6, respectively. A complete CC score of 0-1 was achieved in 507 (56.9%) patients. The median overall survival durations were 34.0 ± 7.8 and 20.8 ± 13.2 months in the colon and rectal groups, respectively (P = 0.367). The 1-, 2-, 3-, 4-, and 5-year survival rates in the colon and rectal groups were 79% and 68%, 63% and 68%, 50% and 51%, 44% and 10%, and 44% and 0%, respectively. In multivariate analysis, the location of the primary tumor did not affect survival (P = 0.597; 95% confidence interval [CI] = 0.237–2.291); however, the postoperative PCI strongly predicted long-term survival (P = 0.001; 95% CI = 3.715–255.547). Conclusion: The management of CRC with PC remains challenging. CRS-HIPEC can provide similar survival benefits when applied to PC of rectal origin than when applied to PC of colon origin. The usage of mitomycin-C for HIPEC yields to a comparable survival benefit and a safe therapeutic option. However, the indication should be only extended to highly selective patients considering the possibility of adequate cytoreduction and performed in experienced centers.