Background: Generating hepatocytes with complete liver functions is still a challenge and developing more functional hepatocytes is needed. Objective: To compare various differentiation factors and protocols and introducing a preferable protocol to differentiate human-induced pluripotent stem cells (hiPSCs) into hepatocyte-like cells (HLCs). Methods: After 3 days of the endoderm differentiation of hiPSCs, the cells were incubated with 5 hepatocyte differentiation culture media, protocols (P), for 14 days—P1: hepatocyte growth factor and fibroblast growth factor-4 (FGF-4) for the first week and oncostatin-M and dexamethasone for the second week; P2: similar to P1 but FGF4 was used in both the first and second weeks; P3: similar to P1 but FGF-4 was not used; P4: similar to P1 but FGF-4 and dexamethasone were not used; and P5: similar to P1 but FGF-4 and oncostatin-M were not used. After 17 days, characterization was done by qRT-PCR, immunofluorescence and ELISA. Results: The mRNA expression levels of hepatocyte markers (albumin, cytokeratin-18, tyrosine aminotransferase, hepatocyte nuclear factor-4α, cytochrome-P450 7A1) increased significantly (p<0.05) in the differentiated cells by 5 different protocols. Furthermore, significant protein expression and secretion of albumin were detected in the differentiated cells by 5 different protocols. In P3, the differentiated cells had the highest exhibit of hepatocyte characteristics and in P4 they had the lowest. Moreover, in P1 and P2 similar results were observed. Conclusion: Since P3 gave us the best results among all protocols, we recommend it as an efficient protocol to differentiate the functional HLCs from hiPSCs, which can improve cell therapies.