Retinoic acid (RA) is a natural derivative of vitamin A which regulates the growth and differentiation of epithelia. We have previously proposed that RA participates in compensatory kidney growth and reported that RA inhibits rat mesangial cell growth. This paper describes the effects of RA on a human renal adenocarcinoma cell line (PAD) under different growth conditions, and its interactions with epidermal growth factor (EGF). PAD cells were shown to express RA receptors α and β by Northern blot analysis. In serum free cultures, addition of RA (10-7 M) markedly increased thymidine incorporation by PAD cells (155 ± 7% mean ± SE vs. control in 6 separate experiments; P < 0.0001). RA also caused a significant increase in thymidine incorporation by PAD cells under conditions of rapid growth in serum supplemented medium (115 ± 2% vs. control; P < 0.001). RA by itself was unable to reverse contact inhibition of PAD cell growth (NS vs. control), but it synergistically enhanced the mitogenic effect of EGF on confluent monolayers (110 ± 0.6% vs. EGF alone; P < 0.05). Northern blot analysis demonstrated that PAD cells express EGF receptor mRNA, and this was not significantly modified by the addition of RA. Growth arrested (serum starved) PAD cells expressed RAR-α mRNA which was upregulated eightfold at three hours following the addition of 10% FCS. Thus, our data show that RA is directly mitogenic for serum starved human renal adenocarcinoma cells and that it exerts complex modulation of cell growth in the presence of EGF and serum components.