Patients with relapsing-remitting multiple sclerosis (MS) are at risk of converting to a secondary progressive disease course. To assess the relationship between brain magnetic resonance imaging (MRI) findings and onset of secondary progression, we reanalyzed the initial brain MRI scans of 90 relapsing-remitting MS patients, who were clinically followed up for at least 10 years (median 14 years) after their scan, for the number and volume of T2 lesions, and for two measures of brain atrophy (bicaudate ratio and third ventricle width). The relationship to development of secondary progression was studied with Cox regression models and Kaplan-Meier survival analyses. At the end of follow-up, 36 patients had become progressive. The presence of more than 10 T2 lesions more than doubled the risk of becoming secondary progressive (hazards ratio 2.36; 95% CI 1.19-4.66). When at least one of the 10 lesions was confluent the risk increased to 3.51 (1.64-7.50). The hazards ratio for an estimated T2 lesion load of more than 800 mm(3) was 2.11 (1.07-4.16). Linear brain atrophy measures were not predictive. Our data show a relationship between the extent of brain T2 lesions and the onset of secondary progression in MS.