Background and Objective: Neuroendocrine differentiation has not been proved to have effects in behavior of colorectal carcinomas. The aim of this study was Immunohistochemical evaluation of neuroendocrine differentiation in colorectal cancer. Patients and Methods: In this cross-sectional study, 83 paraffin blocks from patients admitted in Rasoul-e-akram Hospital, Tehran, Iran, during 2003 to 2008, were evaluated in Pathology Department. All sections were stained with immunohistochemistry method for neuron specific enolase (NSE) and Chromogranin A(CgA). Data were analyzed using SPSS 12.0. Results: Median age of patients was 56 yr. Forty four cases (53%) were female. According to TNM staging system, 11% of cases were in stage I, 29% in IIa, 7% in IIb, 2% in IIIa, 23% in IIIb, 24% IIIc and 2% were in stage IV. Thirteen cases (16%) were NSE positive, 15 cases (18.1%) were CgA positive. Two, 8 and 5 percent of the patients in grade I, II and III were CgA positive, respectively. Two, 6 and 5 percent of the patients in grade I, II and III were NSE positive. In grades II and III, NSE and CgA were significantly higher than grade I (P<0.001). CgA incidence was higher significantly in mucinous carcinomas (P<0.05). Conclusion: Less than 20% of colorectal cancers showed neuroendocrine differentiation. There was no significant relationship between NSE and CgA incidence with stage or tumor site. There was a relationship between histologic grade and above-mentioned markers; this finding may help us in our knowledge about tumor behavior.