We evaluated antibody persistence up to 5 years postvaccination with a quadrivalent meningococcal serogroups A, C, W and Y tetanus toxoid conjugate vaccine (MenACWY-TT), and subsequent booster responses to MenACWY-TT in healthy US children. In the initial phase II, open, multicenter study (NCT00471081), 349 infants were randomized (1:1) to receive MenACWY-TT (1 or 2 doses). In the follow-up study (NCT00718666), we evaluated antibody persistence at years 1, 3 and 5 by serum bactericidal assay using human complement (hSBA). At year 5, children received a booster dose of MenACWY-TT. We compared their immune responses at 1 month postbooster with those from 100 age-matched, meningococcal naive children, who received a primary MenACWY-TT dose. We recorded solicited adverse events for 4 days and unsolicited adverse events for 31 days, followed by an additional 5-month extended safety follow-up. At year 5, ?64.0% of 1-dose and ?74.6% of 2-dose recipients had hSBA titers ?8 for MenC, MenW and MenY. For MenA, 31.7% of 1-dose and 38.0% of 2-dose recipients had hSBA titers ?8. One month postvaccination, all booster dose recipients and ?78.5% of primary dose recipients exhibited hSBA titers ?8 for all serogroups. Geometric mean titers were higher in primed than in naive children. MenACWY-TT had a clinically acceptable safety profile. With the exception of serogroup W, antibody persistence 5 years after MenACWY-TT vaccination did not differ substantially between children who received 1 or 2 doses in infancy. A booster dose of MenACWY-TT elicited robust anamnestic responses and was well tolerated.