Purpose: The purpose of this study is to assess the short-term morbidity and mortality in patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) with diaphragmatic involvement. Methods: All patients undergoing CRS/HIPEC at a tertiary care institution from April 2007 to October 2013 were retrospectively reviewed. Patients with diaphragmatic disease (Group 1) were compared to those who did not (Group 2). Univariate, propensity score analysis, and multivariate analysis were used to compare groups focusing on postoperative complications. Results: A total of 199 patients underwent CRS/HIPEC. Diagnoses included appendiceal/colorectal cancers (56 %), pseudomyxoma peritoneii (12 %), and gastric cancer (7 %). Group 1 was composed of 89 patients (44.7 %) with diaphragmatic involvement, of which 37.1 % underwent diaphragm stripping and 62.9 % required a full-thickness diaphragmatic resection. Group 1 had longer operative times (p = 0.009), increased transfusion requirements (p = 0.007), less optimal cytoreduction (p = 0.010), longer ICU stay (p = 0.003), and overall hospital stay (p = 0.039). Major complications were significantly higher in Group 1: 26 (29 %) versus 16 (15 %), p = 0.020. Rate of respiratory complications was not different between groups (G1: 14/26, 53.8 % and G2: 6/16, 37.5 %, p = NS). Ninety-day mortality was not significantly different. Diaphragmatic involvement (Estimate 1.235, SE 0.387, p = 0.017) was an independent predictor of 30-day morbidity in patients with <5 organs involved in cytoreduction. Conclusions: Diaphragmatic involvement is associated with higher tumor burden and more complex operations. It is a strong independent predictor 30-day morbidity in patients with <5 organs involved in cytoreduction. However, perioperative mortality rates are not significantly different between the groups, suggesting that diaphragm stripping or resection is warranted in well-selected patients if it allows for complete cytoreduction.