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Background The ASCEND trial did not find benefit of natalizumab during secondary progressive multiple sclerosis compared with placebo; however, its open-label extension suggests this may be obscured by therapeutic lag.We aimed to compare the efficacy of natalizumab and interferon β-1a in slowing disease progression in secondary progressive multiple sclerosis after accounting for therapeutic lag.Methods We analysed pooled data from the ASCEND (natalizumab vs placebo) and SPECTRIMS (interferon β-1a vs placebo) trials. Cumulative hazards of 6-month confirmed disability progression during secondary progressive multiple sclerosis were compared using Cox proportional hazards models adjusted for confounding variables. We accounted for therapeutic lag in each patient based on baseline expanded disability status scale, annualised relapse rate and sex. Differences between SPECTRIMS and ASCEND placebo arms were used to adjust the differences between interferon β-1a and natalizumab arms.Results Baseline characteristics of 1156 patients were similar between SPECTRIMS and ASCEND cohorts, except for a higher proportion of older patients and lower relapse rates in the ASCEND trial. Natalizumab exhibited a lower cumulative hazard of disability progression compared with interferon β-1a (HR 0.15, 95% CI 0.08 to 0.29, p<0.0001). After adjusting for the difference in cumulative hazards between placebo groups (HR 0.36, 95% CI 0.20 to 0.63, p=0.0004), natalizumab remained associated with a lower hazard of disability progression compared with interferon β-1a (HR 0.42, 95% CI 0.22 to 0.77, p=0.0016).Conclusion After accounting for therapeutic lag and differences between ASCEND and SPECTRIMS trials, natalizumab, compared with interferon β-1a, reduces disability progression during secondary progressive multiple sclerosis.