Introduction: Recent reports have shown that smoking has a negative impact on the development and course of multiple sclerosis. Aim: The aim of this multicentre (Bydgoszcz, Zabrze, Białystok, Szczecin) study was to analyse the relationship between smoking and disease activity in patients with relapsing-remitting multiple sclerosis on immunomodulatory therapy. Materials and methods: We evaluated demographic and clinical data, such as sex, age, smoking (pack-years), treatment duration, disability status according to the Expanded Disability Status Scale (EDSS). Furthermore, we determined disease activity based on both the annualised relapse rate (ARR) after one and 2 years of treatment and magnetic resonance imaging findings. The obtained data were analysed statistically. Results: The study group included 114 patients: 57 (50%) non-smokers and 57 (50%) smokers. Mean treatment duration was 2.46 (±1.23) years, mean EDSS was 2.12 (±1.03), and ARR at treatment initiation was 1.46 in smokers vs. 1.36 in non-smokers. New magnetic resonance demyelination lesions were found after 1 year of treatment in 15 (26.3%) smokers and 8 (14%) non-smokers. Statistical analysis showed significant relationships between smoking and new cerebral lesions in magnetic resonance imaging (r = −0.21, p < 0.05). Conclusions: Smokers on immunomodulatory therapy show marked radiological progression of the disease in the first 2 years of treatment compared to non-smokers.