Background: The purpose of this study was to assess the efficacy of combination therapy with RRx-001, an aerospace-derived macrophage repolarizing agent with epigenetic and vascular normalization properties, plus irinotecan vs. regorafenib plus irinotecan in 3^rd/4^th line metastatic colorectal cancer that previously received treatment with irinotecan. Methods: Between June 2014 and August 2015, 34 patients were enrolled. Therapy consisted of intravenous administration of RRx-001 at 4 mg once weekly until progression followed by intravenous infusion of irinotecan at 180 mg/m² on day 1 in a 21-day cycle vs. 160 mg oral regorafenib daily for 3/4 weeks followed at progression, if applicable, by irinotecan 180 mg/m² on day 1 in a 21-day cycle. Results: The survival follow up for RRx-001 + irinotecan range was approximately 14.5 months (mean 6.0 months, median 5.0 months, standard deviation 4.5 months). The survival follow up for regorafenib range was approximately 10.8 months (mean 4.5 months, median 4.0 months, standard deviation 3.9 months). The median survival time was 8.6 months for RRx-001 + irinotecan and 4.7 months for regorafenib. The median progression free survival was 7.5 months for RRx-001 + irinotecan vs. 1.7 months for regorafenib. In addition, the toxicity profile of RRx-001 + irinotecan was dramatically improved compared with regorafenib. The regorafenib arm was terminated for futility at interim analysis, after which any enrolled patients only received RRx-001 co-infused with an aliquot of autologous blood to evaluate the safety of that method of administration. Conclusions: The results of this trial demonstrate improved efficacy and efficacy of RRx-001 + irinotecan compared with regorafenib in patients with metastatic colorectal cancer. Clinical trial information: NCT02096354