The aims of this study were: (i) to compare health-related quality of life (HRQoL) as measured by the Medical Outcomes Study Short Form 36-Item Health Survey (SF-36) in a population sample of migraine headache sufferers and controls without migraine; (ii) to assess the relationship of HRQoL and work-related disability attributed to headache in a population sample. The study was conducted in two phases. First, a population-based, telephone interview survey of 5769 residents of greater London, England was conducted to identify individuals with migraine headache (cases) and controls without migraine. In the second stage, in-person interviews were conducted in a matched sample of 200 migraine cases and 200 controls selected from survey respondents. At the beginning of the in-person interview, participants were asked to complete the SF-36. In addition, a work-related disability score based on the telephone interview was defined as the number of lost work days or days when usual activity was reduced by 50% or more over the previous year. The disability score was trichotomized as mild (n = 98), moderate (n = 49), and severe disability (n = 49). Compared with controls, individuals with migraine headache scored significantly lower in eight of the nine domains of the SF-36 as well as in the overall Physical Component Summary (PCS) score and Mental Component Summary (MCS) score. Further, among migraine sufferers, each of the disability groups scored significantly lower in seven of the nine domains and in the summary scales. Scores showed greater reductions in HRQoL for the moderate and severe disability groups vs. the mild disability group in five of nine scales and in the Total Physical Summary score. We conclude that, in a population-based sample of migraine headache sufferers, individuals with migraine headache have lower HRQoL scores compared with controls. Moreover, among individuals with migraine headache, work-related disability is associated with lower HRQoL scores. Specifically, individuals classified with moderate to severe work-related disability had lower HRQoL scores than those classified with low disability.