Endothelial activation is a key feature of multiple sclerosis (MS) pathogenesis. It is modulated by interferon beta‐1b (IFNB‐1b) treatment in relapsing–remitting MS (RRMS) patients. This particular pharmacodynamic effect still has to be proven in primary progressive MS (PPMS). In the current study, serum concentrations of soluble vascular cell adhesion molecule‐1 (sVCAM‐1) and sE‐selectin were analyzed longitudinally in 18 PPMS patients before, during and after 12 months of treatment with IFNB‐1b. During drug therapy there was a significant early and sustained increase of sVCAM‐1 (overall P < 0.0001). Flu‐like symptoms induced by IFNB‐1b and also concomitant infections were associated with higher sVCAM‐1 levels. Neutralizing antibodies to IFNB‐1b were associated with lower sVCAM‐1 levels. In conclusion, IFNB‐1b modulates the adhesion cascade in patients with PPMS in a similar way it does in RRMS. Nevertheless, a clinical effect of IFNB in PPMS still has to be proven in a randomized controlled clinical trial.