OBJECTIVE: We investigated whether demographic, disease-related, or personal baseline determinants can predict a positive response to energy conservation management (ECM). METHOD: We conducted a secondary analysis of a single-blind, two-parallel-arms randomized controlled trial that included ambulatory adults with severe MS-related fatigue. Therapy responders and nonresponders were categorized by Checklist Individual Strength fatigue change scores between baseline and end of treatment. Logistic regression analyses were used to assess the determinants of response. RESULTS: Sixty-nine participants were included (ECM group, n = 34; control group, n = 35). In the ECM group, fatigue severity, perception of fatigue, illness cognitions about MS, and social support discrepancies were related to the probability of being a responder. CONCLUSION: The results suggest that people with MS-related fatigue who had a less negative perception of fatigue and who perceived fewer disease benefits and a higher discrepancy in social support had the best response to ECM treatment.