OBJECTIVES: To estimate the risk of developing hepatotoxicity with the use of doxorubicin among cancer patients.  METHODS: A nested case-control study was conducted using IMS LifeLink Plus (2006-2013) claims dataset. Types of cancers wherein doxorubicin is likely to be prescribed as an antineoplastic agent were included in the nest. Among the nest, those with hepatotoxicity were categorized as cases and those without were categorized as controls. Hepatotoxicity was defined as a diagnosis of either acute/sub-acute necrosis of liver, or toxic hepatitis, or hepatic coma. Each case was matched up to 5 controls on age, gender, length of pre-event period (+/-90 days), date of event (+/-90 days) and type of cancer. Adjusted and unadjusted conditional logistic regression analyses were conducted to estimate the risk of hepatotoxicity with the exposure to doxorubicin. Sub-group analysis among breast cancer cases was also conducted. Analyses were adjusted for conditions and drugs that are known to be associated with increased risk of hepatotoxicity.  RESULTS: A total of 2462 cases of hepatotoxicity met our inclusion-exclusion criteria among the nest population. Use of doxorubicin increased the risk of hepatotoxicity among all cancer types by 1.26 times compared to those with no doxorubicin use (OR: 1.26, 95% CI: 1.045-1.52). Similarly, among breast cancer patients, use of doxorubicin increased the risk of hepatotoxicity by 1.32 times (OR: 1.315, 95% CI: 1.063-1.627). After adjusting for potential confounders, use of doxorubicin among all cancer types increased the risk of hepatotoxicity by 1.29 times compared to those with no doxorubicin use (OR: 1.293, 95% CI: 1.069-1.563). Likewise, among breast cancer patients, use of doxorubicin increased the risk of hepatotoxicity by 1.33 times (OR: 1.333, 95% CI: 1.075-1.653). CONCLUSIONS: The use of doxorubicin is associated with an increase in the risk of developing hepatotoxicity especially among breast cancer patients.