ImportanceAssessment of additional protection of a booster dose with an inactivated SARS-CoV-2 vaccine is key to developing vaccination strategies for billions of people worldwide who have received the primary 2-dose regimen.ObjectiveTo estimate the relative effectiveness of a booster dose of an inactivated SARS-CoV-2 vaccine against Omicron infection.Design, Setting, and ParticipantsThis cohort study was conducted among primary close contacts without previous SARS-CoV-2 infection identified in Shenzhen, China, between February and October 2022. Multiple strict nucleic acid testing and symptom surveillance for SARS-CoV-2 infection were regularly conducted during the 7-day centralized plus 7-day home-based quarantine.ExposureA booster with an inactivated SARS-CoV-2 vaccine vs no booster after receipt of the primary 2-dose inactivated SARS-CoV-2 vaccine regimen.Main Outcomes and MeasuresThe primary outcomes were overall, symptomatic, and asymptomatic infections. Secondary outcomes were length of incubation and level of cycle threshold values. All the outcomes were assessed during the quarantine period.ResultsAmong 119 438 eligible participants (mean [SD] age, 37.6 [12.0] years; 66 201 men [55.4%]), 86 251 (72.2%) received a booster dose of an inactivated SARS-CoV-2 vaccine and 33 187 (27.8%) did not. A total of 671 cases infected with Omicron BA.2 were confirmed (464 symptomatic and 207 asymptomatic), and no severe infection or death events were observed. At a median (IQR) duration of 111 (75 to 134) days after booster vaccination, the relative effectiveness of a booster was 32.2% (95% CI, 11.3% to 48.2%) for overall infection, 23.8% (95% CI, −8.2% to 46.4%) for symptomatic infection, and 43.3% (95% CI, 12.3% to 63.3%) for asymptomatic infection. The effectiveness against overall infection changed nonlinearly over time following booster vaccination: 44.9% (95% CI, 4.9% to 68.1%) within 60 days, 50.4% (95% CI, 23.7% to 67.7%) at 61 to 120 days, 29.1% (95% CI, −4.8% to 52.1%) at 121 to 180 days, and 19.4% (95% CI, −14.4% to 43.2%) after 180 days (nonlinear P = .03). The effectiveness did not vary significantly according to the interval between booster vaccination and completion of primary vaccination. There was no association of booster vaccination with incubation or cycle threshold values.Conclusions and RelevanceIn this cohort study, a booster dose of an inactivated SARS-CoV-2 vaccine provided additional moderate protection against mild infection for 120 days after receipt, but more research is needed to determine the optimal timing of a booster and its effectiveness in preventing severe infection for a longer duration.