Background: Disability outcome measures in multiple sclerosis (MS) focus heavily on ambulation; however, limitations in performing everyday activities encompass another type of disability. Objectives: The aim of this study was to examine the ability of instrumental activities of daily living (IADL) scale to discriminate between different levels of disability and to predict disability progression. Methods: The North American Research Committee on Multiple Sclerosis (NARCOMS) registry fall 2006 semi-annual survey asked participants to complete the RAND-12, Performance Scales, Patient Determined Disease Steps (PDDS), and IADL questionnaires. We modeled the trajectory of disability change, using the PDDS, over 12 years. Analyses used linear and repeated measures regression methods. Results: Of respondents ( n = 9931), 9559 (96%) completed the PDDS and IADL scale. Respondents were mostly female (76%), Caucasian (92%), and 52.3 (10.5) years old with moderate disability (median PDDS 4 (early cane)). Mean (SD) IADL total score was 20.5 (3.7). Discriminant ability of the IADL scale was higher than other measures considered at higher levels of disability. Adjusted longitudinal models showed that needing greater assistance on IADLs was independently predictive of trajectories of greater disability change. Conclusion: IADL scale had a greater ability to discriminate between higher disability levels than RAND-12 domains. The IADL scale may provide a useful and clinically relevant tool to measure disability in progressive MS populations.