Polyamines are essential for the repair of gastric and duodenal erosions. Concentrated NaCl (3.4 M) given intragastrically damages the oxyntic gland mucosa and increases the activity of gastric mucosal ornithine decarboxylase (ODC), the first rate-limiting enzyme in polyamine synthesis. The nature of the process of restitution of damaged mucosa is not well known, except that cell migration and the actin cytoskeleton play a prominent role. Microtubules are cytoskeletal components essential for cell migration. The present investigation determines the relationship between polyamines, the distribution of microtubules, and gastric healing in mucosa damaged with hypertonic NaCl solution. Rats were fasted for 22 h and then given 1.0 ml of 3.4 M NaCl intragastrically. Animals were killed 1, 2, 4, 8, and 10 h after 3.4 M NaCl. The oxyntic gland mucosa was removed, and tubulin was visualized by immunofluorescence. Microtubule density was increased around and below the damaged mucosa in the upper one-third of the glandular epithelium at 2 and 4 h and returned to near control levels by 10 h. In rats damaged with 3.4 M NaCl and pretreated intraperitoneally with α-difluoromethylornithine (DFMO), a specific inhibitor of ODC, microtubule content was reduced significantly at all time points after NaCl treatment. Addition of spermidine after pretreatment with DFMO and 3.4 M NaCl significantly prevented the effects of DFMO. Colchicine, a potent microtubule-disrupting drug, significantly delayed normal gastric mucosal healing with no effect on ODC activity. These data show that polyamines influence the distribution of microtubules during damage in vivo and indicate a partial mechanism for the dependency of mucosal healing on polyamines.