Background: Universal screening for chronic hepatitis B virus (HBV) infection prior to chemotherapy has been recommended by the Centers for Disease Control. We evaluated the cost-effectiveness of HBV screening prior to chemotherapy given for non-hematopoietic solid tumors (ST). Methods: A decision-analytic model was used to compare the cost-effectiveness of a universal patient screening program conducted as per professional guidelines, versus no screening, in hypothetical patient cohorts beginning adjuvant chemotherapy for early breast cancer or palliative chemotherapy for advanced non-small cell lung cancer. Survival times were extrapolated using Markov models. Probabilities were derived from published studies and costs estimated from the perspective of the Australian health care system. One-way and probabilistic sensitivity analyses were performed, including with the application of an alternative HBV screening strategy. Results: Using an incremental cost-effectiveness ratio (ICER) threshold of $50,000 Australian dollars per life year (LY) saved, universal HBV screening was not cost-effective for adjuvant patients (ICER $88,173/LY, 13% probability of being cost-effective), palliative patients ($1,343,482/LY, 0%) or pooled (all) ST patients ($149,771/LY, 1%). Sensitivity analyses found screening approached cost-effectiveness among adjuvant patients with the highest reported rates of undiagnosed chronic HBV (65%; $51,979/LY) or HBV reactivation with chemotherapy (41%; $48,799/LY). Cost-effectiveness was also significantly influenced by HBV population prevalence, but insensitive to the relative risk reduction with prophylaxis or prophylactic antiviral drug used. An alternative screening strategy employing HBSAg testing only produced the most economically favorable results, with ICER $30,075/LY (80% probability) for adjuvant patients and $51,115/LY (43%) for the pooled cohort. Conclusions: Universal HBV screening conducted as per current guidelines is not cost-effective in patients with non-hematopoietic ST. Screening may be economically favorable in selected patient subpopulations and/or with simplification of the screening strategy.