Quality of life data from randomized trials are lacking in older patients with metastatic colorectal cancer (mCRC). In the randomized NORDIC9-study, reduced-dose S1+oxaliplatin (SOx) showed superior efficacy compared to full-dose S1 monotherapy. We hypothesized that treatment with SOx does not result in inferior quality of life. Patients with mCRC aged ≥ 70 years and that were not a candidate for standard combination chemotherapy were included and randomly as-signed to receive either S1 or SOx. The EORTC QLQ-C30 questionnaire was completed at baseline, after 9, and 18 weeks. The primary endpoint was global Quality of Life (QoL) at 9 weeks. For statistical analysis, a non-inferiority design was chosen applying linear mixed effects models for repeated measurements. The results were interpreted according to statistical significance and anchor-based, clinically relevant between-group minimally important differences (MID). A total of 160 patients aged (median (Interquartile range (IQR))) 78 years (76–81) were included. The QLQ-C30 questionnaire was completed by 150, 100, and 60 patients at baseline, at 9, and 18 weeks, respectively. The difference at 9 weeks in global QoL was 6.85 (95%CI-1.94; 15.65) and 7.37 (0.70; 14.05) in the physical functioning domain in favor of SOx exceeding the threshold for MID. At 18 weeks, the between-group MID in physical functioning was preserved. Dose-reduced combination chemotherapy may be recommended in vulnerable older patients with mCRC, rather than full-dose monotherapy.