Background: Facial port-wine stains (PWS) are considered by some an aesthetic skin problem, yet impact on quality of life (QoL) has not been objectively documented. Objective: We sought to (1) characterize the effect of PWS on QoL in adults, (2) to identify the clinical and demographic factors that affect QoL, and (3) to compare our results with QoL studies in other skin conditions. Methods: In total, 244 adults with facial PWS completed an online QoL survey, which included the Skindex-29 instrument. Results: QoL in adults with facial PWS was diminished, especially from an emotional perspective. Variables associated with reduced QoL in all Skindex-29 subdomains included comorbid depression, limited facial mobility, and presence of other skin conditions. Persons with hypertrophy had more emotional and symptomatic impairment. The composite dermatologic-specific QoL scores were similar to those of cutaneous T-cell lymphoma, rosacea, alopecia, and vitiligo. Limitations: Selection bias was a potential limitation, as participants were primarily recruited from patient support groups. Conclusion: Our analysis demonstrates that the presence of a facial PWS has a significant negative impact on QoL. Dermatologists caring for patients with PWS should inquire about QoL, provide appropriate support and resources, and consider QoL when discussing treatment options and obtaining authorization for these procedures.