Infection with influenza B viruses of both the B/Yamagata/16/88-like and the B/Victoria/2/87-like lineage induced hemagglutinin (HA)–specific antibodies with antibody-dependent cellular cytotoxicity (ADCC) activity in humans. Only antibodies directed to the HA stalk were capable of mediating ADCC and displayed lineage cross-reactivity. Abstract Influenza A virus (IAV) and influenza B virus (IBV) cause substantial morbidity and mortality during annual epidemics. Two distinct lineages of IBV are distinguished, based on variation in hemagglutinin (HA): B/Victoria/2/87-like (B/Vic) and B/Yamagata/16/88-like (B/Yam). Here, we show that, in humans, primary IBV infection with either lineage induces HA-specific antibody-dependent cellular cytotoxicity (ADCC)–mediating antibodies. IBV infection induced antibodies specific to the HA head and stalk, but only HA stalk–specific antibodies mediated ADCC efficiently and displayed cross-reactivity with IBV of both lineages. This corresponds to recent findings that 2 points of contact between the effector and target cell (ie, HA and sialic acid, respectively, and the fragment crystallizable Fc domain and Fcγ receptor IIIα, respectively) are required for efficient ADCC activity and that antibodies specific for the receptor-binding site located in the head domain of HA therefore fail to mediate ADCC. Potentially, ADCC-mediating antibodies directed to the HA stalk of IBV contribute to cross-protective immunity to IBV of both lineages.