As a therapeutic or chemopreventative agent for various cancers, all-trans retinoic acid (atRA) has been reported to inhibit growth, induce apoptosis or cause differentiation. It was found that atRA could protect hepatocellular carcinoma (HCC) cells against cell death induced by serum starvation. Furthermore, it was found that atRA could enhance cell adhesion, but had no effect on the cell cycle and apoptosis. Using an Illumina Human HT-12 v4 expression microarray, 207 upregulated and 173 downregulated genes were identified in HepG2 cells treated with atRA. The most upregulated genes are cytochrome P450 family 26 subfamily A polypeptide 1 (CYP26A1), histidine triad nucleotide binding protein 3 (HINT3), miR-1282 and cytochrome P450 family 26 subfamily B polypeptide 1 (CYP26B1), which showed more than fivefold greater expression. Using Gene Ontology analysis, the greatest significance was found in extracellular-matrix-related molecular functions and the cellular component in upregulated genes. The upregulation of collagen 8A2 (COL8A2) was further confirmed using quantitative RT-PCR and western blotting. Knockdown of COL8A2 blocked enhancement in the early stage of cell adhesion by atRA treatment. Re-expression of COL8A2 in COL8A2-knocked-down HCC cells reversed the effect of small interfering RNA–COL8A2. In addition, COL8A2 could increase HCC cell migration and invasion. Thus, COL8A2 was identified as the key protein involved in the enhancement of cell adhesion of atRA under serum-free conditions. In conclusion, atRA protects HCC cells against serum-starvation-induced cell death by enhancing cell adhesion, and COL8A2 plays an important role in HCC cell migration and invasion.