The molecular mechanisms underlying premalignant gastrointestinal diseases, such as ulcerative colitis and Barrett's esophagus, remain unknown. For this reason, the expression of the protooncogene c-Ha-ras was studied in ulcerative colitis and Barrett's esophagus. Total cellular RNA was extracted from different regions of the gastrointestinal tract in these two diseases. Expression of c-Ha-ras was greater in proximal than in distal colon and undetectable in Barrett's esophagus. These regional differences in expression were not seen with the control gene beta-actin or with the protooncogenes c-myc and p53. In order to evaluate structural factors contributing to expression, amplification and methylation of c-Ha-ras DNA were studied in these tissues by Southern and slot blotting. No amplification of c-Ha-ras or six other protooncogenes was detected. These data suggest tissue-specific regulation of c-Ha-ras expression in the gastrointestinal tract in certain premalignant disease states.