Background: Colorectal cancer (CRC) is a common human malignancy. Epidermal growth factor receptor (EGFR) is expressed in wide variety of human malignancies and is of some therapeutic and prognostic utility. The relationship between EGFR expression and regional lymph nodes involvement, and tumor grade in CRC has not been cleared, thus we decided to show it in a case-control study. Material and Methods: We chose paraffin-embedded tissue blocks of 46 CRCs with regional lymph nodes involvement as case group, and 46 CRCs without lymph nodes involvement as control group and then performed immunohistochemical staining for both groups. Moderate to strong, and complete staining of more than 10% of tumor cells was regarded as EGFR-positive. In analysis, P-value less than 0.05 was considered as significant. Results: EGFR expression was positive in 80.4% and 56.5% of patients in the case and the control groups, respectively, which the difference between them was statistically significant. EGFR was positive in 48% of grade I, 60% of grade II and 100% of grade III tumors. Conclusions: EGFR expression had relationship with lymph node involvement and tumor grade in CRC. Also, lymph node-involved CRCs showed higher scores of EGFR staining than control group. Thus, EGFR may be an additional factor to develop more aggressive CRCs and may predict the probability of lymph node involvement in these tumors.