OBJECTIVES:  The objective of this study is to assess the association between the use of orlistat and the risk of acute liver injury. METHODS:  A self-controlled case series (SCCS) study was conducted by using Truven MarketScan® Commercial Claims data (2003-2004). Patients prescribed at least one prescription of orlistat and experienced an acute liver injury during the study period were included. Conditional Poisson regression model was used to calculate the incidence rate ratios comparing the risk of acute liver injury during periods of orlistat exposure with periods of no exposure. RESULTS: A total of 159 patients were included in this SCCS study. With the SCCS study design to remove the effect of differences among patients, we did not detect the association between the orlistat exposure and the risk of acute liver injury. Compared to the absence of orlistat exposure period, there was no statistically significant increased risk of acute liver injury during the first 30 days treatment of orlistat (incidence rate ratio (IRR), 1.07; 95% confidence interval (CI), 0.52-2.20). The similar results were found for other time periods: 90 days before the first orlistat prescription (IRR, 1.12; 95% CI, 0.72-1.75), 31-61 days of orlistat treatment (IRR, 0.49; 95% CI, 0.12-1.99), 61-90 days of orlistat treatment (IRR, 0.54; 95% CI, 0.13-2.21), post-exposure interval (IRR, 0.88; 95% CI, 0.38-2.03), and more than 90 days orlistat use (IRR, 0.77; 95% CI, 0.38-1.56). CONCLUSIONS: The significant association between the orlistat exposure and the risk of acute liver injury was not detected, even though it may be due to small sample size with the low statistical power in this SCCS study. With the safety concern of acute liver injury events in patients prescribed orlistat, caution is advised for physicians in the use of orlistat. Future research is needed to guide clinical decision making.