Perineural invasion (PNI) may influence the prognosis after resection of colorectal cancer (CRC); whether this is a definite prognostic factor remains controversial. This study determined the clinicopathologic factors associated with oncologic outcome after radical resection of stage II CRC, focusing on PNI. We retrospectively reviewed 341 consecutive patients who underwent curative surgery for stage II CRC between January 2001 and December 2006. Of these, 278 patients (81.5%) received postoperative 5-fluorouracil-based chemotherapy. The oncologic outcomes and the risk factors for recurrence were analyzed. PNI was detected in 57 of 341 patients (16.7%) and was significantly associated with depth of tumor invasion (P = .035) and positive lymphovascular invasion (P < .001). Multivariate analyses revealed that PNI was a significant independent prognostic factor for disease-free survival, not for overall survival. With a median follow-up period of 57.6 months, the 5-year disease-free and overall survival rates of the patients were 80.2 and 82.6%, respectively. The 5-year disease-free survival of the PNI-negative group was significantly higher than that of the PNI-positive group (P < .001). Within the PNI-positive patients, those receiving chemotherapy had significantly higher 5-year disease-free survival than the others (P = .023). This study illustrates the value of PNI as a prognostic factor for stage II CRC. Moreover, PNI-positive patients should be considered for postoperative chemotherapy.