Key PointsQuestionAre antibody levels associated with protection against infection with the SARS-COV-2 Omicron variant?FindingsThis cohort study that included 2310 adults found that the odds of infection and of substantial symptomatic disease significantly decreased for each 10-fold increase in preinfection immunoglobin G titers and for each 2-fold increase in neutralizing antibody titers.MeaningThese findings suggest that antibody titers were associated with protection against infection with the Omicron variant of SARS-CoV-2 and against symptomatic disease once infected.