Neutralizing antibodies against Mayaro virus mediate protection via Fc effector functions. Antibody neutralization of a virus in vitro is often associated with protection against viral exposure in vivo, but the mechanisms operational in vivo are often unclear. By investigating a large number of antibodies, Earnest et al. (https://doi.org/10.1084/jem.20190736) show the importance of antibody effector function in neutralizing antibody protection against an emerging alphavirus in a mouse model.