We estimated vaccine effectiveness (VE) of the BNT162b2 (Pfizer-BioNTech, https://www.pfizer.com) booster dose against SARS-CoV-2 infection and reduction of complications (hospitalization, severe disease, and death) among breakthrough cases in persons in Israel >16 years of age for <20 weeks. VE estimates reached 96.8% (95% CI 96.0%–97.5%) for persons 16–59 years of age and 93.1% (95% CI 91.8%–94.2%) for persons >60 years of age on week 3. VE estimates remained at these levels for 8 weeks in the 16–59 age group and 11 weeks in those >60. A slow decline followed, becoming more pronounced in the last 2–3 weeks of evaluation. Estimates in the last week of evaluation were 77.6% (95% CI 68.4%–84.2%) and 61.3% (52.5%–68.4%) for persons 16–59 years and >60 years, respectively. The more pronounced VE decline coincided with rapid increase in Omicron variant activity. Rate reduction of breakthrough complications remained moderate to high throughout the evaluation.