Although 12 g/day sulbactam/ampicillin (SBT/ABPC) is approved in Japan, differences in the frequency of adverse effects induced by conventional (≤6 g/day) and high (≥9 g/day) doses remain unclear. We performed a retrospective observational study on SBT/ABPC-treated hospitalized adult patients with pneumonia from October 2015 to January 2018 to compare the safety between high and low doses. Patients were divided into high-dose (≥9 g/day, n = 200) and low-dose (≤6 g/day, n = 246) groups. We used logistic regression to determine propensity scores for the high-dose and low-dose groups and compared the incidence of adverse effects after propensity score adjustment (n = 200 in each group). Following propensity score adjustment, the frequency of elevated alanine aminotransferase (ALT) level was still significantly higher in the high-dose group than in the low-dose group (21% versus 11%, p = 0.006). In contrast, the frequencies of elevated alkaline phosphatase, aspartate aminotransferase, and serum creatinine levels and decreased white blood cell and platelet counts, and incidence of anemia, were not. Changes in blood urea nitrogen levels, erythrocyte count, and hematocrit were not significantly different between the two dose groups. There were two cases of rash reported to the Pharmaceuticals and Medical Devices Agency as an adverse effect in the high-dose group. Thirty-day mortality rates were not significantly different after propensity score adjustment. Our analysis suggests that an increase in the ALT grade was more frequent in patients treated with a daily dose of SBT/ABPC of ≥9 g.