Background Comorbidities occur frequently in persons with multiple sclerosis (MS). The aim of the present study was to determine the prevalence of the most common comorbidities in the population of MS patients in Belgrade, Serbia. Material and methods Data on diagnosed and fully documented comorbidities were taken from the Belgrade MS population registry. The list of explored comorbidities included cardiovascular, malignant, and autoimmune diseases; psychiatric disorders; epilepsy; and type 2 diabetes. In the data analysis, crude, age- and gender-specific, and age-adjusted prevalence was calculated. Additionally, comorbidities were analyzed in patients with various MS phenotypes. Results The most prevalent group of comorbidities were psychiatric (prevalence (Prev) = 20.59%, 95% CI 19.10–22.17) and cardiovascular comorbidities (Prev = 15.23%, 95% CI 13.93–16.63). The most prevalent single comorbidities were depression (Prev = 11.82%, 95% CI 10.64–13.11) and hypertension (Prev = 11.41%, 95% CI 10.25–12.68). Type 2 diabetes was significantly more prevalent in patients with primary progressive MS compared with the patients with relapsing-remitting and secondary progressive MS ( p < 0.001). We found statistically significant positive correlation between number of comorbidities and progression index ( p < 0.001). Patients treated with disease-modifying therapies (DMTs) had significantly higher risk of developing comorbidity, after treatment initiation, compared with those who were untreated ( p = 0.001). Conclusions Our study demonstrated high prevalence of comorbidities in persons with MS, with psychiatric and cardiovascular diseases being the most common. Furthermore, our findings confirmed the association of comorbidities with progression of disability and emphasized their role in treatment decision-making in MS.