To investigate the role of miR-215 in the relapse following radical surgery of colorectal cancer patients. The clinical data and surgical frozen tumor tissues were retrospectively collected from 125 stage II/III colorectal cancer patients, which contained 60 patients who relapsed and 65 patients who did not relapse within 3 years after surgery. The expression of miR-215 was determined by real-time PCR, and the relationship between miR-215 expression and the relapse was analyzed statistically. miR-215 was downregulated in relapsed patients compared to nonrelapsed patients (P = 0.001). The low expression of miR-215 was significantly correlated with a high probability of 3-year relapse (P = 0.001), which was more obvious in stage III patients (P < 0.001). The multivariate analysis showed that miR-215 expression could function as an independent predictive marker for relapse. It seemed that patients with high expressions of miR-215 could benefit from 5-fluorouracil-containing adjuvant chemotherapy without significant difference, whereas this phenomenon was reverse in patients with low expressions of miR-215. Our study highlighted for the first time that miR-215 could function as a potential predictive marker for relapse following radical surgery of colorectal cancer, and the possible correlation between miR-215 and 5-fluorouracil-containing adjuvant chemotherapy would be validated in the future.