Objectives- To evaluate clinical and MRI effects of natural interferon β treatment in both relapsing-remitting (RR) and secondary-progressive (SP) multiple sclerosis patients. Material and methods- A double-blind, randomized trial of natural interferon β (nIFN-β) in 58 ambulatory patients with RR and 40 with SP multiple sclerosis. Forty-nine patients (29 RR and 20 SP) were treated with intramuscular nIFN-β 6 MIU three times a week for 24 months and 49 control patients were treated with placebo. Results- Primary clinical endpoints were differences in exacerbation rates and proportion of patients remaining exacerbation-free. There were no significant baseline differences between the treated and placebo groups. In the treated RR group a significant reduction in exacerbation rate, an increase in the probability of remaining exacerbation-free, and an improvement in mean EDSS were found at 24 months. MRI activity and total lesion burden were significantly reduced in treated RR patients. In the SP group, nIFN-β produced a significant reduction in EDSS score, a significant reduction in active lesion number, a marginally significant favourable difference in total lesion burden but no significant effect on the number of gadolinium-enhancing lesions. Side effects were transient and mild in treated patients. Conclusions- These observations confirm that nIFN-β is a promising and well-tolerated treatment for either RR or SP MS patients.