Objective: To investigate disease activity and disability progression following pregnancy-related discontinuation of natalizumab (NTZ) in patients with relapsing-remitting MS. Methods: A retrospective cohort study of clinical and radiologic data in patients who discontinued NTZ for pregnancy-related reasons. Results: Twenty-two pregnancy-related NTZ discontinuations in 17 patients were evaluated. The median time to conception was 3.4 months. Relapses were more frequent in patients in whom conception did not occur within 6 months (p = 0.022). Confirmed disability progression occurred in 27.3% and was associated with time to conception (p < 0.001). Conclusions: Early conception after NTZ discontinuation is associated with a reduced risk of disease activity and disability progression. Continuation of NTZ treatment until confirmed pregnancy should be considered in patients with previously active MS. However, the advantages of continuing the drug until pregnancy should be balanced against the uncertainties in postnatal outcomes.