Shortly after reaching confluency, canine MDCK cells enter a prolonged state of basal growth with doubling times of 200-300 hours. These values are similar to those commonly exhibited by in vivo solid tumors at clinically relevant sizes. By comparison with rapidly growing sparse density cultures, the postconfluent monolayers displayed a pronounced resistance to deazauridine, deoxyspergualin, and 5-fluorouridine. Drug concentrations required for unit levels of effect increased from several fold to several orders of magnitude as cells entered high density basal growth. This high density chemoresistance was observed for both growth inhibition and cytotoxicity, but was much more pronounced with the former. Dose-response curves were biphasic, suggesting that growth inhibition and cytotoxicity may be mediated by different mechanisms of drug action. The pronounced chemoresistance of postconfluent MDCK monolayers is similar to that encountered with many clinical solid neoplasms. It suggests that postconfluency monolayers, like multicellular spheroids and cellular multilayers, may provide better in vitro models of solid tumor chemosensitivity than subconfluent monolayer and suspension cultures.