Abstract Background Reports on associations between azole antifungal medications and acute liver injury are inconsistent and have not been based on liver-related laboratory tests. We evaluated incidence rates of acute liver injury associated with oral azole antifungals. Methods We conducted a cohort study among Kaiser Permanente Northern California members who initiated an oral azole antifungal in an outpatient setting during 2004-2010. We determined development of: (1) liver aminotransferases >200 U/L, (2) severe acute liver injury (coagulopathy with hyperbilirubinemia), and (3) acute liver failure. We calculated incidence rates of endpoints. Cox regression was used to determine whether chronic liver disease was a risk factor for outcomes. Results Among 195,334 azole initiators (178,879 fluconazole; 14,296 ketoconazole; 1653 itraconazole; 478 voriconazole; 28 posaconazole), incidence rates (events/1000 person-years 95% confidence intervals (CIs)) of liver aminotransferases >200 U/L were similarly low with fluconazole (13.0 11.4-14.6), ketoconazole (19.3 13.8-26.3), and itraconazole (24.5 10.6-48.2). Rates were higher with voriconazole (181.9 112.6-278.0) and posaconazole (191.1 23.1-690.4), but comparable. Severe acute liver injury was uncommon with fluconazole (2.0 1.4-2.7), ketoconazole (2.9 1.1-6.3), and itraconazole (0.0 0.0-11.2), but more frequent with voriconazole (16.7 2.0-60.2) and posaconazole (93.4 2.4-520.6). One patient developed acute liver failure due to ketoconazole. Pre-existing chronic liver disease increased risks of aminotransferases >200 U/L (hazard ratio 4.68 95% CI, 3.68-5.94) and severe acute liver injury (hazard ratio 5.62 95% CI, 2.56-12.35). Conclusions Rates of acute liver injury were similarly low for fluconazole, ketoconazole, and itraconazole. Events were more common among voriconazole and posaconazole users but were comparable. Pre-existing chronic liver disease increased risk of azole-induced liver injury.