Purpose <p>Neurofibromatoses (NF; NF1, NF2-related schwannomatosis, and other forms) are incurable genetic disorders linked to poor quality of life (QoL). Limited research exists on social support as a protective factor for QoL in NF. This secondary analysis examined whether baseline social support moderates QoL outcomes in individuals with NF.</p> Methods <p>Participants (<i>N</i> = 228, M_age=41.5, 75% female) were randomized to 3RP-NF (a mind-body resiliency intervention) or HEP-NF (control). Measures of social support and QoL (environmental, social, physical, psychological) were collected at baseline, post-test, and 12-month follow-up.</p> Results <p>Individuals with higher baseline social support reported consistently higher QoL across both interventions, achieving clinically meaningful improvement, while those with low social support did not. No significant 3-way interactions were found between time, social support, and group from baseline to post-test (ps = 0.13–0.83) or follow-up (ps = 0.21–0.69). However, exploratory analyses showed a significant interaction between time and baseline social support for the 3RP-NF group in social, environmental, and psychological QoL at post-test (ps = 0.02–0.05), with a sustained effect at follow-up for social QoL (<i>p</i> = .01). No such effects were found in the HEP-NF group (ps = 0.25–0.68).</p> Conclusion <p>In adults with NF, baseline social support moderates social and environmental QoL in mind-body interventions. Enhancing social support early may particularly benefit individuals with initially low support, though further research is needed to identify effective strategies for achieving clinically meaningful changes.</p> Trial registration <p>ClinicalTrials.gov Identifier NCT03406208. <a href="https://clinicaltrials.gov/study/NCT03406208">https://clinicaltrials.gov/study/NCT03406208</a></p>