Objective The aim of this study was to compare self-perceived health between migraine and early stages of relapsing-remitting multiple sclerosis (RRMS) and to explore whether and how accurate those health domains predict overall quality of life. Methods Ninety patients aged 18–55 years were enrolled in this cross-sectional study. Thirty follow-up outpatients were recruited with migraine (with or without aura), 30 patients with RRMS, and 30 healthy subjects. They were asked to complete the Health status questionnaire (SF-36) and Personal Wellbeing Index (PWI). Results Patients with RRMS and migraine had significantly worse self-reported health regarding role limitation due to physical problems and general health than the healthy control group. Additionally, migraine patients had more bodily pain, while RRMS patients expressed more difficulties regarding physical functioning. Differences between migraine and RRMS patients were not significant. Hierarchical regression analysis revealed that role limitation due to physical problems, mental health, and general health represents significant predictors of overall quality of life. Conclusions Migraine may affect quality of life similarly to early stages of RRMS. Bio-psycho-socio-medical understanding of the two diseases and their impact on patients QoL should be reconsidered.