Background <p>Dialysis patients are at high risk for hepatitis B virus (HBV) infection. Intramuscular administration of HBV vaccination has shown limited responsiveness and durability of seroprotection in dialysis patients. Intradermal (ID) HBV Sci-B-Vac vaccination with imiquimod (Toll-like receptor 7 agonist) pretreatment was reported to be safe and improve seroprotection. This study aimed to evaluate the cost-effectiveness of ID administration of HBV Sci-B-Vac with pre-treatment imiquimod cream in dialysis patients from the perspective of US healthcare providers.</p> Methods <p>A lifetime Markov model was used to estimate outcomes in a hypothetical cohort of serologically negative dialysis patients with: (1) HBV Sci-B-Vac administered intradermally with pre-treatment imiquimod (IMQ) cream (IMQ + ID group), (2) HBV Sci-B-Vac by intradermal injection alone (ID group), and (3) HBV Sci-B-Vac by intramuscular injection alone (IM group). Main results included direct medical costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER).</p> Results <p>QALYs in the IMQ + ID group (2.9763) were the highest, followed by the ID group (2.9751) and the IM group (2.9740). The ID group (more costly and totals less QALYs versus IMQ + ID) was strongly dominated by the IMQ + ID group, and was eliminated from the cost-effectiveness analysis. The ICER of the IMQ + ID group versus the IM group (17,032 USD/QALY) was lower than the willingness-to-pay (WTP) threshold (50,000 USD/QALY) and remained lower than the WTP threshold in the one-way sensitivity analysis. The probabilities of IMQ + ID, IM, and ID groups to be cost-effective at a WTP of 50,000 USD/QALY were 85.06%, 14.86%, and 0.08%, respectively.</p> Conclusion <p>ID administration of HBV Sci-B-Vac with pre-treatment IMQ cream in serologically negative dialysis patients was the cost-effective strategy.</p>