Background: Most of the patients receiving regorafenib do not seem to benefit from this treatment approach and are therefore exposed to unnecessary toxicity. Angiogenesis and inflammation-related factors may have a relevant role in modulating the activity of anti-angiogenetic drugs such as regorafenib. In our study, we investigated LDH serum levels, platelet, neutrophil, and lymphocyte counts, and neutrophil-to-lymphocyte ratio (NLR) in predicting clinical outcomes for colorectal cancer patients receiving regorafenib. The final aim was to individuate an easy to use and reliable selection tool for these patients in the clinical practice. Methods: We collected LDH serum levels, neutrophil, lymphocyte, and platelet counts within one month before the start of regorafenib in 208 pretreated metastatic colorectal cancer patients. Cut-off values were calculated by ROC curve analysis. Survival analysis was performed by Kaplan-Meier method, and multivariate analysis by Cox method. Results: At multivariate analysis: high platelet count (p=0.0439), low lymphocyte count (p=0.0013), and high NLR (p=0.0237) were related to worse overall survival (OS); high neutrophil count and high NLR (p=0.0058) were related to worse progression free survival (PFS). Among 52 (25%) patients who were negative for all risk factors, a significant correlation was found with improved OS and PFS if compared with the group of patients with at least one risk factor. In particular, median OS was respectively 15.9 vs. 3.1 months (HR: 3.81, 95% CI: 2.32-4.82, p<0.0001) whereas median PFS was 5.9 vs. 2.1 months (HR: 2.62, 95% CI: 2.06-3.86, p<0.0001). Conclusions: We can speculate that colorectal cancer patients showing high neutrophil, high platelet, low lymphocyte count or high NLR may not be optimal candidates for regorafenib treatment. After confirmation in further prospective series, these clinical factors could play a role in the treatment strategy process.