Neurofibromatosis type 1 (NF1) is a genetic condition characterized by numerous somatic manifestations. The psychosocial burden in adults has rarely been studied. We examined the prevalence of self-reported impairment of quality of life (QoL), symptoms of anxiety and depression and need for support, associated with disease severity and visibility. We conducted a nationwide cross-sectional study of all 467 adults with NF1 diagnosed between 1977 and 2016 at one of the two national centers for rare diseases in Denmark. A total of 244 (56% response rate) completed a questionnaire that included standard measures of QoL, symptoms of depression and anxiety, indicators of disease-related severity, visibility, and need for professional support. Associations between disease severity and visibility and psychosocial burden were analyzed in descriptive and multivariate models. We observed impaired QoL (mean = 81.3; 95% CI, 76.2; 86.4); 19% reported symptoms of depression (mean = 5.7; SD = 5.4), and 15% reported anxiety (mean = 5.1; SD = 5.2) at a clinical level. Adults with NF1 also reported requiring professional support for physical, psychological, and work-related problems. Disease severity and (partly) visibility were significantly (p < .0001) associated with psychosocial well-being and a requirement for support. This study provides new understanding of the factors associated with impaired QoL, indicating that follow-up care should be optimized into adult life.