Background: Natalizumab is approved for treatment of active forms of relapsing–remitting multiple sclerosis (MS) based on a pivotal phase III study comprising patients aged 18–50 years. The effect of natalizumab has not been specifically studied in older patients. Objective: We analyzed age-dependent effects on treatment-related outcome measures in 1872 patients, 189 of whom were aged 50 or more, included in the Swedish post-marketing natalizumab surveillance program. Methods: In three MS centers registry data for patients aged >50 years were validated. Results: At baseline older patients had longer disease duration, higher Expanded Disability Status Scale (EDSS) and lower Symbol Digit Modality Test (SDMT) scores than younger patients. The influence from natalizumab on outcome measures was significantly reduced and 18.7% of patients >50 years stopped treatment for lack of effect compared to 7.7% in the younger age group. At baseline, the cerebrospinal fluid levels of the chemokine CXCL13 and the leukocyte cell count were negatively correlated with age in a smaller subgroup of patients. Conclusion: These results were in agreement with previous findings suggesting that inflammation is more pronounced in younger patients and therefore the beneficial effects of potent anti-inflammatory treatments are subsiding with older ages.