Background <p>Peritoneal metastases from colorectal cancer (pmCRC) are associated with poor prognosis. Neoadjuvant chemotherapy followed by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has improved survival in these patients. However, few studies have evaluated the influence of radiological and pathological responses on overall survival (OS) and recurrence-free survival (RFS) in this population.</p> Objective <p>The objective of this study was to assess these prognostic markers in patients with pmCRC who received neoadjuvant chemotherapy followed by CRS-HIPEC at our institution.</p> Methods <p>A total of 121 patients with pmCRC treated with neoadjuvant chemotherapy followed by CRS-HIPEC from 2012 to 2023 were included. Demographic, clinical, and oncological data were extracted from medical records. OS and RFS were obtained using Kaplan–Meier analysis. Univariate and multivariate Cox regression analyses were done.</p> Results <p>After a median follow-up of 44.6 months, median OS was 47.1 months (95% confidence interval [CI] 32.4–61.6) and RFS was 21.8 months (95% CI 13.7–29.9). No significant difference in OS was observed among patients who achieved a partial response on imaging compared with non-responders (hazard ratio [HR] 0.9; 95% CI 0.5–1.5; <i>p</i> = 0.725). Patients who did not achieve a complete pathological response showed a significant difference in OS, with worse OS (HR 3.4; 95% CI 1.3–8.9; <i>p</i> = 0.012). OS was significantly lower in patients with a peritoneal carcinomatosis index &gt;15 (HR 4.1; 95% CI 1.1–15; <i>p</i> = 0.033).</p> Conclusions <p>Radiological response after neoadjuvant chemotherapy does not significantly affect the OS or RFS of patients with pmCRC. Complete pathological response is a significant prognostic marker for both OS and RFS.</p>