Background. Perineural invasion (PNI) in colon cancer (CC) has been associated with poorer prognosis even in stage II disease (T3-4 N0 M0). The aim of this study is to analyze prognostic histopathologic factors in stage II colon cancer in patients treated with curative surgery as established in National Comprehensive Cancer Network guidelines. Methods. From a prospective database of CC cases, 507 patients with stage I-II disease who had undergone curative resection from January 2000 and December 2012 were identified. Of these patients, 17 % received 5-flurouracil-based adjuvant chemotherapy. Together with demographic and anatomic variables, we also studied perineural and lymphovascular invasion, degree of differentiation, and their correlation with disease-free survival. Results. Perineural invasion was identified in 57 patients (11.2 %) and lymphovascular invasion (LVI) in 82 (16.2 %) of the 507 patients. Perineural invasion was associated with LVI, the depth of invasion of the wall of the colon, and location of the tumor. Overall and disease-free survival of the complete series at 5 and 10 years was 89.5, 85.2, 83.2 and 81.6 %, respectively. In the PNI positive patients, disease-free survival at 5 years was significantly lower than in those without PNI (73.5 vs 88.6 %; p = 0.02). Multivariate analysis showed the presence of PNI to be a significant independent prognostic factor for disease-free survival (p = 0.025). Adjuvant chemotherapy reversed the impact of PNI on 5-to 10-year disease-free survival. Conclusions. PNI a major prognostic and predictive factor in stage II colon cancer, and our results support the use of adjuvant chemotherapy in patients with PNI.