Overuse of stress ulcer prophylaxis has a considerable cost burden on patient and healthcare systems. This study aimed to determine the adherence level of stress ulcer prophylaxis use with American Society of Health-System Pharmacists guidelines in a teaching hospital in Shiraz, Iran. From March to September 2013, we enrolled all eligible patients admitted to the general medical wards of Shahid Faghihi Hospital, Shiraz, Iran. According to American Society of Health-System Pharmacists guidelines, patients who had at least one major or two minor risk factors for stress ulcers and received stress ulcer prophylaxis were labeled as adherent, others were considered nonadherent. During the study period, 441 patients enrolled, of which 257 (58.3%) were women. The mean ±SD age of patients was 54.7 ± 20 years. The mean ±SD length of hospital stay for patients was 11.3 ± 6 days. Overall, 354 patients (80.2%) received proton pump inhibitors as stress ulcer prophylaxis. There were 127 patients who properly received stress ulcer prophylaxis. Total adherence to American Society of Health-System Pharmacists guidelines in our hospital was 28.8%. We observed a high frequency of unnecessary use of stress ulcer prophylaxis in hospitalized, noncritically ill patients with inappropriate continuation after discharge.