It is now well established that clinically stable patients with relapsing-remitting multiple sclerosis have ongoing disease activity when evaluated by serial gadolinium-enhanced (Gd-DTPA) magnetic resonance imaging (MRI) scans. Despite this, the relationship between clinical disease and MRI lesions, though suspected, has not been extensively documented. The relationship between Gd-DTPA MRI lesions and clinical disease was examined in this study of 9 patients with mild relapsing-remitting multiple sclerosis (Expanded Disability Status Scale [EDSS] < 3.5) who had 24 to 37 monthly Gd-DTPA MRI scans, neurological examinations, and EDSS score assignments. The area and frequency of Gd-DTPA lesions were examined during months with and without clinical worsening as measured by EDSS. Forty-one episodes of clinical worsening were noted during the study. A significant association was observed between these periods of clinical worsening and MRI parameters, including increases in total number, number of new lesions, and the total area of enhancement. Logistic regression analysis showed a significant effect of the number and area of Gd-DTPA MRI lesions on both the onset and continuation of clinical worsening, confirming an important relationship between clinical disease and an increase in cerebral Gd-DTPA MRI activity. A relationship with long-term disability was suggested, but cannot be confirmed without longer follow-up of these patients.