Background: Patients with chronic hepatitis B virus infection (HBV) are at risk for hepatotoxicity (HT) from viral reactivation during chemotherapy courses (TC). This can be minimized with antiviral prophylaxis (AV). Screening for HBV before TC remains controversial. Methods: A retrospective observational data only study was conducted at a Northern California integrated health care delivery system examining patients undergoing TC between 2000 and 2010. Patients were categorized as HBV positive (HBV+) if they had a positive HBsAg, HBeAg, or HBV DNA any time before and 1 year post TC. Grade 3 and 4 HT was determined using the National Cancer Institute Common Toxicity Criteria, with adaptation for those who had baseline abnormal liver function tests. We excluded patients with HIV, co-infection with both HBV and hepatitis C, and HBsAb of unclear provenance. Two control groups (CTRL1 and CTRL2) were established that had tested negative for HBV and HCV 1996 through 1 year after the last TC: CTRL1 tested negative for both before TC initiation (index TC); CTRL2 tested negative for one pre and the other post index TC or both at any time after index TC. AV prophylaxis (AVP+) was defined as anti-HBV medication given before HT; the remainder were AVP-, including those given AV after HT. Electronic medical record review was conducted on all HBV+ patients. Results: We identified 9,279 patients who received 15,960 TC; 57.8% were female with a mean age of 57.8 (±14.4) at TC initiation. 464 TC were given to 289 HBV+ patients; 22.8% had HT, with 7 deaths from HT, all AVP-. The rate of HT in the controls was 9.9% in CTRL1 (34/343), 12.6% in CTRL 2 (1907/15,153). Conclusions: These findings support the recommendation that all patients planning to receive TC should be screened for HBV. Those found positive should receive AV prophylaxis during therapy.