Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide. Intrahepatic cholangiocarcinoma (ICC) accounts for about 10-15% of all primary hepatic malignancy. Combined hepatocellular carcinoma and cholangiocarcinomas (cHCC-CCs) are rare malignancies representing 1.0-4.7% of all primary liver cancers. ICC and cHCC-CC preoperative diagnosis is desirable because frequency of lymph node metastasis. Also they have been considered a contraindication for liver transplantation (LT).The study aimed to assess the importance of CA19-9 in diagnosis of cHCC-CC "non-invasively" in patients with typical radiological features of HCC which may alter the interventional procedure. This observational cross-sectional study was conducted on 62 patients with typical radiological criteria of HCC and elevated CA19-9 level, who attended to National Hepatology and Tropical Medicine Research Institute (NHTMRI); Cairo, Benha university hospitals within the period between October 2017 and April 2019. All studied subjects underwent history taking, clinical examination, biochemical workup, tumor markers, abdominal ultrasound, and dynamic study (CT/MRI). Target liver biopsy was done for histopathology and immuno-histochemistry. The studied patients were classified into three groups based on pathological diagnosis. 20 patients were diagnosed as HCC, 40 patients were diagnosed as ICC, and 2 patients were diagnosed as cHCC-CC with statistically significant difference between HCC and ICC as regard CA19-9 and alpha-fetoprotein (AFP). CA19-9 and AFP cut offs were ˃ 64.8 U/mL and ˂ 23.6 ng/mL, respectively favoring the diagnosis of ICC. CA19-9 level was 176.3 and 156.7 U/mL while AFP level was 460 and 170 ng/mL in cHCC-CC cases, respectively. The use of CA19-9 can help in diagnosis of ICC and suspicion of cHCC-CC in cases of typical radiological criteria of HCC.