Purpose The objective of this study was to analyze the role of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy that has developed in the treatment of patients with peritoneal metastasis of non-primary origin. Methods Patients who underwent treatment for secondary gastrointestinal and ovarian malignancies over a 20-year period were reviewed. Survival curves were estimated by the Kaplan-Meier product limit method and the log-rank test was used to assess differences between subgroups. Results The study included 293 patients. The most common histology was ovarian cancer (56.3%). Median PCI was 16 and CC0-1 resection was obtained in 88.1% of cases. Grade III and IV complications occurred in 12 patients (4.1%) and 47 patients (16%), respectively. The 30- and 60-day mortality rate was 1.3% (4 patients) and 2.4% (7 patients). Five-year OS was 21.7%, 73.6%, 42.1%, and 0 for colorectal, appendiceal, ovarian, and gastric cancer (p = < 0.0001), respectively, whereas 5-year DFS was 12.4%, 48.4%, 24.3%, and 0 (p = < 0.0001), respectively. Survival outcomes were significantly higher for CC0 in each subgroup of patients. Conclusion Despite being a complex procedure, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy should be considered a safe treatment with acceptable postoperative morbidity and mortality rates, if performed in high-volume centers. Good survival outcomes have been increasingly obtained in selected patients with peritoneal metastasis of non-primary origin.