Hepatitis B viral (HBV) mutants can emerge in patients as a result of selection pressure from treatment options. Some mutations that occur in the immunodominant "a" determinant of hepatitis B surface antigen (HBsAg) can present as false negative results in HBsAg immunoassays. The mutation position in HBsAg and the type of mutation impacts immunoassay performance. HBsAg mutants will continue to emerge in response to selection pressure, therefore an appropriate HBV immunoassay-testing algorithm needs to be established to ensure their detection. Mutant surveillance programs can also contribute to our understanding of the changing epidemiology of HBV infection.