Background and purpose To predict disability and cognition in multiple sclerosis (MS) after 6 and 12 years, using early clinical and imaging measures. Methods A total of 115 patients with MS were selected and followed up after 2 and 6 years, with 79 patients also being followed up after 12 years. Disability was measured using the Expanded Disability Status Scale (EDSS); cognition was measured only at follow‐up using neuropsychological testing. Predictors of interest included EDSS score, baseline brain and lesion volumes and their changes over 2 years, baseline age, clinical phenotype, sex and educational level. Results Higher 6‐year EDSS score was predicted by early EDSS score and whole‐brain volume changes and baseline diagnosis of primary progressive MS (adjusted R2 = 0.56). Predictors for 12‐year EDSS score included larger EDSS score changes and higher T1‐hypointense lesion volumes (adjusted R2 = 0.38). Year 6 cognition was predicted by primary progressive MS phenotype, lower educational level, male sex and early whole‐brain atrophy (adjusted R2 = 0.26); year 12 predictors included male sex, lower educational level and higher baseline T1‐hypointense lesion volumes (adjusted R2 = 0.14). Conclusions Patients with early signs of neurodegeneration and a progressive disease onset were more prone to develop both disability progression and cognitive dysfunction. Male sex and lower educational level only affected cognitive dysfunction, which remains difficult to predict and probably needs more advanced imaging measures.