Local and systemic reactions and health impacts reported during the week after second booster dose vaccination were described for v-safe registrants aged ≥50 years who reported receiving a second booster during March 29–July 10, 2022, ≥4 months after their first booster dose this analysis was further limited to registrants who received mRNA vaccines for all doses (both homologous and heterologous) and completed at least one daily health survey after receiving their second booster dose and at least one survey after a previous vaccine dose. For reports of myocarditis and pericarditis, rare adverse events that have been associated with mRNA COVID-19 vaccines, CDC sought information about the clinical course of each case and determined whether the CDC myocarditis case definition was met. CDC physicians reviewed all available information for each decedent to form an impression about the cause of death. For this analysis, death certificates and autopsy reports were requested for any report of death. †† Reports of serious events to VAERS were reviewed by CDC and FDA physicians to form a consensus clinical impression based on available data. ¶ VAERS reports of hospitalization, prolongation of hospitalization, life-threatening illness, permanent disability, congenital anomaly or birth defect, or death are classified as serious.** VAERS staff members assign Medical Dictionary for Regulatory Activities preferred terms (MedDRA PTs) to the signs, symptoms, and diagnostic findings included in VAERS reports. VAERS accepts reports of postvaccination adverse events from health care providers, vaccine manufacturers, and members of the public. § CDC’s v-safe call center contacts registrants who indicate that medical care was sought after vaccination and encourages completion of a VAERS report, if indicated. Health surveys sent daily during the first week after administration of each dose include questions about local injection site and systemic reactions and health impacts. The v-safe platform allows existing registrants to report receipt of a COVID-19 booster dose and new registrants to enter information about all doses received ( ). CDC recommends that health care providers and patients be advised that local and systemic reactions are expected after a second booster dose, and that serious adverse events are uncommon. VAERS received 8,515 reports of adverse events after second mRNA booster doses among adults aged ≥50 years, including 8,073 (94.8%) nonserious and 442 (5.1%) serious events. Among registrants who reported homologous vaccination, injection site and systemic reactions were less frequent after the second booster dose than after the first booster dose. † Among 286,380 v-safe registrants aged ≥50 years who reported receiving a second booster of an mRNA vaccine, 86.9% received vaccines from the same manufacturer for all 4 doses (i.e., homologous vaccination). During March 29–July 10, 2022, approximately 16.8 million persons in the United States aged ≥50 years received a fourth dose. passive surveillance system for monitoring adverse events after vaccination, managed by CDC and FDA ( 3). active surveillance system that monitors adverse events occurring after COVID-19 vaccination. V-safe is a voluntary smartphone-based U.S. To characterize the safety of a second mRNA booster dose among persons aged ≥50 years, CDC reviewed adverse events and health impact assessments reported to v-safe and the Vaccine Adverse Event Reporting System (VAERS) after receipt of a second mRNA booster dose during March 29–July 10, 2022. The Advisory Committee on Immunization Practices (ACIP) recommends that all persons aged ≥5 years receive 1 booster dose of a COVID-19 vaccine after completion of their primary series.* On March 29, 2022, the Food and Drug Administration (FDA) authorized a second mRNA booster dose ≥4 months after receipt of a first booster dose for adults aged ≥50 years and persons aged ≥12 years with moderate to severe immunocompromise ( 1, 2).