Treatment of two nontransformed rat kidney cell lines with either retinoic acid or epidermal growth factor enhances anchor-age-dependent cell growth and reduces cell substratum adhesiveness significantly, whereas the cell morphology is only moderately affected. Simultaneous treatment of these cells with these factors results in a dramatic change in cell morphology and increases cell growth and reduces cell substratum adhesiveness even further. Treatment of nontransformed rat kidney cells with certain retinoids enhances the binding of 125I-labeled mouse epidermal growth factor 2- to 3-fold. Acidition of epidermal growth factor stimulates anchorage-independent growth of these cells. Reti-noids enhance colony-forming ability in soft agar produced by epidermal growth factor, although retinoids by themselves do not affect anchorage-independent growth. Growth in soft agar induced by epidermal growth factor or epidermal growth factor plus retinoic acid treatments appears to be a reversible trait. Acidition of epidermal growth factor stimulates secretion of plasminogen activator, whereas this production is not influenced by retinoids. A transformed rat kidney cell line, which exhibits very low epidermal growth factor binding and grows progressively in soft agar, is not significantly affected by retinoid treatment. © 1983, American Association for Cancer Research. All rights reserved.