The mechanisms of antibiotic adverse effects on gastrointestinal tract functions are not clear. The macrolide antibiotics have wide spectrum of nonantibiotic action. It was shown that they can directly influence on airway epithelium ion transport. In present study we tested the hypothesis that treatment with 15-member macrolide antibiotic azythromycin may affect net water and electrolytes movement across colonic epithelium. Methods: The study was done on male Wistar rats (180-230 g). Azithromycin (15 mg/kg, per.os.) was given orally each day for 5 days. Net water and ion trasport (Na, K, Cl) were evaluated on the 6th day by isolated colonic loop perfusion technique in vivo on anaesthetized rats (urethane, 1.1 g/kg intraperitoneal). The colonic levels of malondialdehyde and the catalase activities by colorimetric assays and superoxide dismutase activity by zymograthy were measured. Blood was obtained by cardiac puncture after terminal CO2 treatment. The blood lipids concentration was evaluated by gas-liquid chromatography. The fecal microflora has been analyzed by bacteriological culture methods. Results: Treatment with azithromycin increased water 2.5-fold (p<0.001), sodium 1.7-fold (p<0.001), chloride absorption 1.3-fold (p<0.05) and decreased potassium secretion (p<0.05). This effect was associated with 2-fold increase growth of Staphylococcus epidermidis, Streptococcus and Candida, while levels of Bifidobacterium and Lactobacillus were unchanged. We found increased catalase (p<0.01) and superoxide dismutase (p<0.05) activity in colonic mucosa after 5 days of azithromycin treatment, while levels of malondialdehyde (the intensity of lipid peroxidation) did not change. Azithromycin did not affect levels of polyunsaturated and unsaturated fatty acids concentration in whole blood of rats. Conclusions: 1) Azithromycin directly affects ion and water transport across colonic epithelium; 2) Therapy with azithromycin evoke pathogenic microflora overgrowth that was followed by oxidative stress in colonic epithelium.