Background Patients with vitiligo experience reduced quality of life. Objective To comprehensively describe the available evidence for psychosocial burden in vitiligo. Methods A systematic review of observational studies and clinical trials identified using PubMed, EMBASE, Scopus, and the Cochrane databases was performed through 1 March, 2021, to assess psychosocial comorbidities in vitiligo. Two independent reviewers performed an assessment of articles and extracted data for qualitative synthesis. Results Included studies (N = 168) were published between 1979 and 1 March, 2021; 72.6% were published since 2010. Disorders including or related to depression (41 studies, 0.1-62.3%) and anxiety (20 studies, 1.9-67.9%) were the most commonly reported. The most prevalent psychosocial comorbidities were feelings of stigmatization (eight studies, 17.3-100%), adjustment disorders (12 studies, 4-93.9%), sleep disturbance (seven studies, 4.6-89.0%), relationship difficulties including sexual dysfunction (ten studies, 2.0-81.8%), and avoidance or restriction behavior (12.5-76%). The prevalence of most psychosocial comorbidities was significantly higher vs healthy individuals. Factors associated with a significantly higher burden included female sex, visible or genital lesions, age < 30 years (particularly adolescents), and greater body surface area involvement, among others. The most commonly reported patient coping strategy was lesion concealment. Limitations Available studies were heterogeneous and often had limited details; additionally, publication bias is possible. Conclusions The results of this systematic review show that vitiligo greatly affects psychosocial well-being. The extent of psychosocial comorbidities supports the use of multidisciplinary treatment strategies and education to address the vitiligoassociated burden of disease. Protocol Registration PROSPERO (CRD42020162223).