We aimed to determine whether the intensity of alanine aminotransferase (ALT) flares during antiviral therapy is associated with the level of hepatitis B surface antigen (HBsAg) decline.Quantitative HBsAg was determined during tenofovir monotherapy or tenofovir plus peginterferon alfa-2a in 201 participants with hepatitis B e antigen-positive or -negative chronic hepatitis B. A multivariable analysis identified factors associated with a shorter time to reduction in HBsAg.Fifty flares occurred during treatment of which 74% were moderate (ALT >5-10 × upper limit of normal) or severe (ALT >10 × upper limit of normal). These flares were associated with greater HBsAg decline compared with no flares. Significantly faster times to HBsAg decline >1 log 10 IU ( P = 0.04) and to HBsAg level <100 IU/mL ( P = 0.01) were observed with severe flares.Flare severity is a potentially important factor associated with shorter time to HBsAg reduction. These findings can be useful when evaluating HBsAg response to evolving hepatitis B virus therapies.