Background: Detection of the primary site of metastatic carcinoma of unknown origin is necessary to help in the choice of the treatment. CDX2 is routinely used in metastatic adenocarcinomas cases for identifying the gastrointestinal origin. HNF4α is a new immunohistochemical marker with a few studies showing that it is expressed in a majority of colorectal adenocarcinomas. Aim: To determine the expression of HNF4α and CDX2 in metastatic carcinoma cases for detection of gastrointestinal origin.  Material and methods: We assessed HNF4α and CDX2 in 60 metastatic carcinoma cases in different organs, which were diagnosed retrospectively. HNF4-α and CDX-2 expressions were evaluated by light microscopic examination of all tissue sections by two different pathologists. The cut-off for positivity of HNF4α and CDX-2 was 1% of stained nucleus of metastatic tumor cells. The sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV) and accuracy of two markers and P value were calculated. Results: The calculated sensitivity, specificity, positive predictive value, negative predictive value and accuracy of HNF4α were 90%, 82.5%, 72%, 94.3% and 85% respectively for diagnosis of colorectal carcinoma metastasis from other metastatic carcinomas. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of CDX2 were 80%, 72.5%, 59.3%, 87.9% and 75% respectively. The P-value for comparing between their expression in metastatic adenocarcinoma from lower GIT and each other groups is less than 0.05. Conclusions: We concluded that HNF4α can be used as a supplementary marker with CDX2 to identify metastatic colorectal adenocarcinoma. HNF4α expression is a highly specific and sensitive marker of colorectal origin.