The spread of tau pathology correlates with cognitive decline in Alzheimer’s disease. In vitro, tau antibodies can block cell-to-cell tau spreading. Although mechanisms of anti-tau function in vivo are unknown, effector function might promote microglia-mediated clearance. In this study, we investigated whether antibody effector function is required for targeting tau. We compared efficacy in vivo and in vitro of two versions of the same tau antibody, with and without effector function, measuring tau pathology, neuron health, and microglial function. Both antibodies reduced accumulation of tau pathology in Tau-P301L transgenic mice and protected cultured neurons against extracellular tau-induced toxicity. Only the full-effector antibody enhanced tau uptake in cultured microglia, which promoted release of proinflammatory cytokines. In neuron-microglia co-cultures, only effectorless anti-tau protected neurons, suggesting full-effector tau antibodies can induce indirect toxicity via microglia. We conclude that effector function is not required for efficacy, and effectorless tau antibodies may represent a safer approach to targeting tau. Display omitted •Antibody effector function and microglia engagement are not required for targeting tau•Full effector and effectorless tau antibodies slow the spread of tau pathology in vivo•Only effectorless anti-tau protects neurons from toxic tau in the presence of microglia•Anti-tau with reduced effector function may represent a safer approach to targeting tau Lee et al. report that antibody effector function is not required for targeting tau with antibodies in vivo and in cultured neurons. The authors propose that reducing anti-tau effector function may offer a safer approach for targeting tau by avoiding engagement of microglia that may induce inflammatory responses.