Methapyrilene (MP) is an antihistamine that was used in sleep aid and allergy medications until it was shown to be a rat liver carcinogen. It was removed from the marketplace, but not until a substantial population had been exposed. The present report describes the opposite actions that MP exerts on non-transformed and transformed rat liver epithelial (RLE) cells. While mitogenically stimulating non-transformed RLEs, MP inhibits growth of transformed RLE cells, suppresses their anchorage independent growth in soft agar, and depresses tumor indices when MP-treated cells are injected into nude mice. This reversion of transformation is induced at MP concentrations as low as 1 and 10µM, which are not toxic; thus, the mechanism of antitransformational action of MP on transformed cells involves a cytostatic effect that is transient and decreases rapidly as MP is removed. This transient, non-genotoxic response implies a reduced risk attributable to MP than might have been implicated on the basis of the original assertion of MP's tumorigenic potential.