Dietary vitamin A and its active metabolites are essential nutrients for many functions as well as potent regulators of gene transcription and growth. Although the epithelium of the small intestine is characterized by rapid and constant renewal and enterocytes play a central role in the absorption and metabolism of alimentary retinol, very little is known about the function of retinoids in the human gastrointestinal epithelium and mechanisms by which programs engage the cell cycle are poorly understood. We have assessed the effects of 10 µM 9- and 13-cis-retinoic acid (RA) on proliferation and differentiation processes, lipid esterification, apolipoprotein (apo) biogenesis and lipoprotein secretion along with nuclear factor gene transcription. Treatment of Caco-2 cells with RA at different concentrations and incubation periods revealed the reduction of thymidine incorporation in 60% pre-confluent or 100% confluent cells. Concomitantly, RA (i) modulated D-type cyclins by reducing the mitogen-sensitive cyclin D1 and upregulating cyclin D3 expressions; and (ii) caused a trend of increase in p38 MAPK, which triggers CDX2, a central protein in cell differentiation. RA remained without effect on lipoprotein output and apo synthesis, even for apo A-I that possesses RARE in its promoter. RA, in combination with 22-OH, could induce apo A-I gene expression without any impact on apo A-I mass. Only the gene expression of PPAR, RAR and RAR was augmented and no alteration was noted in PPAR, PPAR, LXR, LXR, and RXRs. Taken together, these data highlight RA-induced cell differentiation via specific signalling without a significant impact on apo A-I synthesis.