The purpose of the study was to evaluate the efficacy and tolerability of S-1 monotherapy in metastatic colorectal cancer (CRC) patients who have failed the standard oxaliplatin-based or irinotecan-based chemotherapy. From 2007 to 2010, metastatic CRC patients who received S-1 monotherapy as salvage treatment were identified from tumor registry at Samsung Medical Center. All patients received ≥ second-line treatment for CRC. S-1 was administered orally from day 1 to day 14, every 3 weeks. The dose of S-1 for each patient was determined according to body surface area (BSA) as follows: for BSA < 1.25 m(2), 80 mg/day; for 1.25 m(2) < BSA < 1.5 m(2), 100 mg/day; and for BSA > 1.5 m(2), 120 mg/day divided by 2 doses. The median age of the 19 patients was 59 years (range: 33-77). Fourteen (73.7%) of 19 patients received S-1 monotherapy as third-line treatment after failing oxaliplatin-based or irinotecan-based chemotherapy. Previous regimens prior to S-1 therapy were as follows: FOLFOX, XELOX, FOLFIRI, XELOX + avastin, and cetuximab + irinotecan. The median number of administered S-1 courses given in the entire studied population was 3 cycles (1-10 cycles). Three patients had confirmed partial response (PR) after 3 cycles of S-1 treatment. After a follow-up duration of 22.3 months (range: 6.7-32.6 months), median time to progression (TTP) was 2.1 (95% CI, 1.8-4.2) months. Median overall survival was 11.3 months (95% CI, 8.8-16.8) from the time of S-1 chemotherapy administration. Two patients had grade 1 hand-foot syndrome (HFS) after first and 2nd cycles of treatments, respectively, but treatments were continued without developing further adverse events. The salvage S-1 monotherapy in metastatic colorectal cancer patients who failed irinotecan-based or oxaliplatin-based chemotherapy was moderately effective and well tolerated.