Rett syndrome (RTT) is a rare neurodevelopmental disorder of genetic origin characterized by chronic low-grade inflammation, immune imbalance, and frequently associated with compromised respiratory function. During the COVID-19 pandemic, individuals with RTT were classified as high-risk and invited to follow stringent vaccination protocols that included multiple booster doses. However, the immune response elicited by vaccination in this population has never been systematically investigated. Here, we provide the first characterization of spike-specific antibody and memory B cell responses in 23 RTT patients following two or three doses of SARS-CoV-2 mRNA vaccines. RTT patients developed spike-specific IgG levels comparable to those observed in healthy female controls (GMT 8476 [range 5120-20480] and 9213 [640-81920] after the first two vaccine doses, respectively). The frequencies and phenotype of spike-specific memory B cells were also similar between RTT and controls (mean frequency of 1.3 ± 0.6 and 1.6 ± 1.1, respectively) and these cells displayed functional reactivity upon antigenic stimulation in vitro. The assessment of vaccine-induced immunity in RTT addresses a critical knowledge gap by demonstrating the ability of these patients to develop an immune response to mRNA vaccination, thereby providing insights that may inform tailored vaccination strategies and improve understanding of immune competence in this rare disorder.