Background: Clinical trials in metastatic colorectal cancer (mCRC) investigating systemic and local treatment options are usually conducted irrespective of sex. However, sex-associated differences relating to safety and efficacy in the treatment of mCRC are of gaining interest. Methods: The SIRFLOX trial investigated the efficacy and safety of adding radioembolization using yttrium-90 resin microspheres (SIRT) to standard fluorouracil, leucovorin, and oxaliplatin (FOLFOX)–based chemotherapy in patients with previously untreated mCRC comparing it to standard treatment with FOLFOX-based chemotherapy. In this post-hoc analysis, the study population was stratified for sex (male versus female) using Propensity Score Matching (PSM) with baseline variables with difference (p-value < 0.20) in a gender specific comparison serving as matching covariates (age, BSA, sidedness, bilirubin). Groups were matched in a 1:1 ratio, with the nearest calculated propensity logit, with a caliper width of ≤0.20 of the SD of the propensity score logit. Evaluated efficacy endpoints were progression-free survival (PFS, primary endpoint of the trial) and overall survival (OS). Results: 356 (67.2%) male and 173 (32.6%) female patients were randomized and treated in the SIRFLOX trial. In the overall study population, there was no difference regarding PFS or OS between male and female patients. No difference in PFS and OS between male (n = 101) and female (n = 101) patients could be observed independently of treatment arm. After PSM, female patients showed significant benefit regarding PFS from SIRT + chemotherapy compared to chemotherapy alone (12.2 [9.9-17] vs. 9.9 [7.5-12.7], p = 0.047) that translated into a trend to longer OS (27.3 [25.6-36.5] vs. 23.7 [17.8-28.8] months, p = 0.094, HR 0.68 [0.43-1.10]) while male patients did not show a difference regarding PFS and OS between treatment arms (p = 0.170, HR 1.41 [0.87-2.10]). In the experimental arm, female patients had significantly longer OS compared to male patients (27.3 [25.6-36.5] vs. 21.0 [17.9-26.7] months, p = 0.031, HR 0.64 [0.42-0.96]). Sex did not impact on OS in the chemotherapy arm (p = 0.410, HR 1.22 [0.76-2.02]). Conclusions: In the SIRFLOX trial, female patients seem to benefit from the addition of SIRT to chemotherapy regarding PFS and OS. This was not observed in male patients. To our knowledge, this is the first analysis to show sex-differences in the application of SIRT in patients with mCRC. Our results support the development of specific protocols according to sex. Clinical trial information: NCT00724503.