Background: Sensitivity data from a head‐to‐head comparison study in South Africa were used to compare the efficacy of the Ultrio Plus assay in individual‐donation (ID) and minipool (MP)4 and MP8 formats with that of TaqScreen MP6 in preventing hepatitis B virus (HBV) transmission risk.Study Design and Methods: The replicate nucleic acid test (NAT) results on 106 HBV NAT (Ultrio)‐yield samples and 29 HBV DNA (Ultrio)‐negative, hepatitis B surface antigen (HBsAg)‐positive samples were used to determine the viral load in copies/mL against the Eurohep HBV standard by probit analysis. Random viral load distributions were established in 32 pre‐HBsAg window period (WP), 15 post‐HBsAg WP, and 56 occult HBV infection (OBI) donations. Regression analysis of log viral load and Poisson distribution statistics of infectious HBV particles in blood components was used to predict infectivity and efficacy of NAT options in removing HBV transmission risk.Results: For red blood cell transfusions (20 mL of plasma), the modeling predicted an Ultrio Plus ID‐NAT efficacy of 68 and 83% in removing WP and (antibody to hepatitis B surface antigen–negative) OBI transmission risk, respectively, compared to 52 and 49% by TaqScreen MP6. For 200 mL of fresh‐frozen plasma the estimated efficacy levels by these ID‐ and MP6‐NAT options reduced to 57 and 44% for WP and to 67 and 34% for OBI donations, respectively.Conclusion: The efficacy of the currently available commercial NAT systems in reducing HBV transmission risk is mainly driven by the pool size and the transfusion plasma volume. The modeled OBI transmission risk and NAT efficacy levels were in line with those recently reported in three lookback studies and give more insight in the incremental safety provided by HBsAg and antibody to hepatitis B core antigen testing of ID‐NAT screened blood.