In herbivorous hindgut-fermenting rodents, the oral administration of antibiotics targeting primarily Gram-positive and anaerobic flora has been reported to cause fatal dysbiosis, and their use is contraindicated in these species. Azithromycin has good activity against Gram-positive aerobic bacteria and excellent activity against anaerobic bacteria, which is also the majority of the physiological flora of the hindgut-fermenting rodents’ cecal and colonic microflora. Therefore, the purpose of this retrospective study was to evaluate the use and adverse effects of oral azithromycin in guinea pigs and chinchilla patients seen at the University of Wisconsin-Madison over a 25-year period. 101 guinea pigs and 30 chinchillas were included in this study, and otitis media in guinea pigs and dental disease in chinchillas were the most common indications for treatment. The median azithromycin dose was 30 mg/kg PO q24h in both species. Minor adverse effects occurred in 6% of guinea pigs (6/101), with hyporexia being reported in all six cases. In addition, in 3 of these cases, diarrhea and weight loss were reported. One guinea pig (1/101) developed severe adverse effects (typhlitis) during its third course of azithromycin and was euthanized. There were no documented adverse effects of azithromycin prescribed in chinchillas within 4 weeks of administration. Based on this retrospective study, orally administered azithromycin appears to be well-tolerated in guinea pigs and chinchillas.