Previous studies suggested that the incidental use of β-blockers might influence clinical outcome in solid tumors. We assessed the correlation between the incidental use of β-blockers and clinical outcome in colorectal cancer patients treated with first-line chemotherapy alone or in combination with bevacizumab in metastatic colorectal cancer patients. We collected data from 235 metastatic colorectal cancer patients treated with first-line chemotherapy alone (128 patients) or with bevacizumab (107 patients). Patients were stratified for clinical factors such as β-blockers use, age, sex, and site of metastases, previous adjuvant chemotherapy and ECOG performance status. In the chemotherapy alone group patients receiving β-blockers showed an improved overall survival (median OS 41.3 vs 25.7 months, P = 0.03, HR: 2.26, 95% CI: 1.05-3.24). A significant relationship with improved response rate was also evident for B-blocker users (P = 0.044). On the contrary in the β-blockers users group treated with chemotherapy in combination with bevacizumab we observed a trend toward a worse overall survival although nonstatistically significant (median OS 18.5 vs 23.6 months, HR: 0. 89, 95% CI: 0.38-2.03, P = 0.77). Our analysis confirmed a potential prognostic role for the use of β-blockers in colorectal cancer patients treated with chemotherapy. Our findings also suggest a potential worse outcome for patients on β-blockers receiving bevacizumab. Future prospective studies should include the incidental use of β-blockers as stratification factor for clinical outcome.