OBJECTIVES: Emerging data suggest that even mild or subclinical mobility loss associated with multiple sclerosis (MS) may adversely affect health-related quality of life (HrQoL). We evaluated the impact and timing of mobility impairment on HrQoL. METHODS: The North American Committee on Multiple Sclerosis (NARCOMS) registry was used to conduct a cross-sectional study of participants who completed the biannual update and supplemental Spring 2010 surveys. The NARCOMS Performance Scale for mobility was used to grade severity of mobility impairment. HrQoL assessments included the Short Form(SF)-12, physical and mental subscales (PCS and MCS), the EuroQoL (EQ)-5D, EQ-Visual Analog Scale (VAS), and SF-6D. RESULTS: A total of 3483 registrants completed both surveys. Compared with those rating themselves as “normal” (n=628) on the mobility performance scale, participants describing their disability as “minimal” (n=566), “mild” (n=535), “occasional support usage” (n=535), “frequent cane usage” (n=527), “severe” (n=543), and “total” (n=105) each reported poorer HrQoL scores on the PCS and MCS (PCS range: 53.6-30.5, MCS range: 46.8-40.3; p<0.001 for all). The largest relative decrement in PCS and MCS came at the transition from “normal” to “minimal” (PCS: 15.1%, MCS: 6.2%) and “minimal” to “mild” mobility impairment (PCS: 15.4%, MCS: 5.9%), with the detrimental effect of poorer mobility more profound on the PCS, and little effect on the MCS after the earlier stages of mobility impairment. Poorer health utility was also reported in participants in impaired mobility categories compared to “normal” when examined using each of the utility measures (EQ-5D range: 0.89-0.53, EQ-VAS range: 0.83-0.55, SF-6D range: 0.78-0.58; p<0.001 for all). The largest decrements in utility came at the transition from “normal” to “minimal” (9.6%-10.3%) and “minimal” to “mild” mobility impairment (an additional 8.6%-10.7%). CONCLUSIONS: These data suggest that mobility impairment may negatively affect HrQoL, with the most profound decrements occurring at earlier stages of mobility loss.