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Purpose: The primary purpose of this study was to determine the extent to which health factors, functional measures, and pulmonary impairment explain performance on 6-Minute Walk Test (6MWT) distance in ambulatory persons with multiple sclerosis (MS). Another purpose was to determine the effect of disability and age on 6MWT performance and explanatory factors., Methods: A cross-sectional study design was used to evaluate factors that explain performance on the 6MWT in 64 community-dwelling persons with MS-related disability (Expanded Disability Status Scale [EDSS] 3.8±1.6). Of the 64 participants, 43 (67.2%) exhibited mild disability (EDSS <4.0) and 21 (32.8%) had moderate disability (EDSS 4.0-6.5). A regression analysis compared 6MWT performance to measures of health factors (EDSS, number of medications, number of comorbidities, resting HR, systolic and diastolic blood pressure [BP]); physical performance (functional stair test [FST], sit-to-stand test [SST], static standing balance [BAL], Fatigue Severity Scale [FSS], Activities-specific Balance Confidence [ABC] Scale); and pulmonary function (forced expiratory volume in 1 second [FEV(1)], forced vital capacity [FVC], maximal voluntary ventilation [MVV], maximal inspiratory pressure [MIP], maximal expiratory pressure [MEP])., Results: EDSS, ABC, FST, SST, BAL, MVV, MIP, and MEP were significantly associated with 6MWT distance after adjusting for age. Multiple step-wise linear regression analysis revealed that ABC, FST, and BAL were significant and independent explanatory factors of 6MWT distance. ABC and FST explained 75% of the variance in 6MWT performance (R(2)=0.75). Curvilinear regression analysis revealed that the FST is the most significant explanatory factor for 6MWT distance, explaining 79% of the variance (R(2)=0.79)., Conclusions: 6MWT performance in persons with MS was explained by balance confidence (ABC) and stair-climbing ability (FST). The ABC and FST may be practical clinical measures for explaining walking ability and determining risk for disablement in persons with MS.