Background: Several guidelines recommended less intensive chemotherapy for vulnerable patients (pts) with metastatic colorectal cancer (mCRC). However, data in a real-world setting are insufficient particularly for second- or later-line therapies. Methods: This is a multicenter retrospective study of vulnerable pts who were defined to be intolerant to intensive therapy. Vulnerable pts with unresectable mCRC who received vulnerable regimens fluoropyrimidines (FP) with or without biologics, reduced-dose doublet regimens with or without biologics, and anti-epidermal growth factor receptor (anti-EGFR), as first-line therapy between June 2015 and December 2018 were included. Results: A total of 210 pts from 15 Japanese hospitals were enrolled. Their median age, 78 years (range 28-90); male, 57%; ECOG PS 0/1/2, 28/51/21%; right-sided primary tumors, 35%; primary tumor resection, 76%; RAS mutant, 51%. Intolerance to intensive therapy was attributable to older age in 69% of pts, poor PS in 17%, liver and/or renal failure in 24%, and concomitant disease in 30%. First-line regimens such as FP with or without biologics were given to 68%, reduced-dose doublet regimens with or without biologics to 24%, and anti-EGFR monotherapy to 8%. For all pts, the median time to treatment failure (TTF) and overall survival (OS) were 7.6 and 21.4 months, respectively. The response rate (RR) was 31% and the disease control rate was 73%. Despite having a higher RR in doublet regimens with or without biologics, there were no survival differences between FP and doublet regimens (RR 26% vs. 45%, p = 0.03; median TTF 8.2 vs. 7.1 months, p = 0.22; and median OS 23.0 vs. 21.7 months, p = 0.37). Multivariate analysis revealed that ECOG PS2, older age (≥ 80), the presence of ascites, and the number of metastatic sites ≥ 2 were significantly associated with worse OS. Following first-line therapy failure in 195 pts, 74 (38%), 24 (12%), and 13 (7%) pts received vulnerable regimens, full-dose doublet regimens with or without biologics (fit regimens), and other regimens, respectively, as second-line therapy. The median TTF and OS were 4.4 and 13.7 months in vulnerable regimens and 2.6 and 11.7 months in fit regimens, respectively. In 84 pts (43%) who received best supportive care (BSC), the median OS was 3.5 months. Following second-line therapy failure in 84 pts who underwent vulnerable regimens as second-line therapy, third-line chemotherapy was administered to in 42 pts with a median OS of 13.7 months. Conclusions: The efficacy of first-line therapy for vulnerable pts in a real-world setting was comparable to previous studies. Second-line therapy demonstrated clinically significant antitumor activity. Nonetheless, the number of patients who received second- or later-lines chemotherapy was low, and survival in pts who received BSC was dismal.