Background: We propose a phase-III, randomized controlled trial (RCT) that examines the effectiveness of a behavioral intervention based on social cognitive theory (SCT) and delivered through the Internet using e-learning approaches for increasing physical activity and secondary outcomes (e.g., symptoms) in a large sample of people with multiple sclerosis (MS) residing throughout the United States. Methods/design: The proposed phase-III trial will use a parallel group, RCT design that examines the effect of a 6-month behavioral intervention for increasing physical activity and secondarily improving mobility, cognition, symptoms, and quality of life (QOL) in persons with MS. The primary outcome is accelerometer-measured moderate-to-vigorous physical activity (MVPA). The secondary outcomes include self-report measures of physical activity, walking impairment, cognition, fatigue, depression, anxiety, pain, sleep quality, and QOL. The tertiary outcomes are mediator variables based on SCT. Participants (N = 280) will be randomized into behavioral intervention (n = 140) or attention and social contact control (n = 140) conditions using computerized random numbers with concealed allocation. The conditions will be administered over 6-months by persons who are uninvolved in screening, recruitment, random assignment, and outcome assessment. There will be a 6-month follow-up without intervention access/content. We will collect primary, secondary, and tertiary outcome data every 6 months over the 12-month period. Data analysis will involve intent-to-treat principles and latent growth modeling (LGM). Discussion: The proposed research will provide evidence for the effectiveness of a novel, widely scalable approach for increasing lifestyle physical activity and improving secondary outcomes and QOL in persons with MS.