This phase 1 clinical trial evaluated the safety, reactogenicity, and immunogenicity of mRNA-1647, a messenger RNA (mRNA)-based cytomegalovirus (CMV) vaccine, in CMV-seronegative and -seropositive adults. Participants were randomly assigned to receive 30, 90, 180, or 300 μg of mRNA-1647 or placebo on a 0-, 2-, and 6-month schedule and were followed for 12 months after the last dose. A total of 154 participants (80 CMV-seronegative and 74 CMV-seropositive) were enrolled, with 118 randomized to mRNA-1647 and 36 to placebo. No serious adverse events were reported, and most adverse reactions were mild. Increased neutralizing antibody, binding antibody, and antigen-specific cell-mediated responses were observed across all mRNA-1647 treatment groups, regardless of CMV serostatus. The trial demonstrated that mRNA-1647 has an acceptable safety profile and elicits humoral and cellular immune responses in adults. These findings support further research on mRNA-1647 as a potential approach to prevent CMV infection.This phase 1 clinical trial evaluated the safety, reactogenicity, and immunogenicity of mRNA-1647, a messenger RNA (mRNA)-based cytomegalovirus (CMV) vaccine, in CMV-seronegative and -seropositive adults. Participants were randomly assigned to receive 30, 90, 180, or 300 μg of mRNA-1647 or placebo on a 0-, 2-, and 6-month schedule and were followed for 12 months after the last dose. A total of 154 participants (80 CMV-seronegative and 74 CMV-seropositive) were enrolled, with 118 randomized to mRNA-1647 and 36 to placebo. No serious adverse events were reported, and most adverse reactions were mild. Increased neutralizing antibody, binding antibody, and antigen-specific cell-mediated responses were observed across all mRNA-1647 treatment groups, regardless of CMV serostatus. The trial demonstrated that mRNA-1647 has an acceptable safety profile and elicits humoral and cellular immune responses in adults. These findings support further research on mRNA-1647 as a potential approach to prevent CMV infection.