Objectives –  The aim of this investigation was to evaluate factors that might influence the health‐related quality of life (HRQoL) in multiple sclerosis (MS) patients in Serbia. Materials and methods –  This cross‐sectional study was performed on a group of 156 patients with MS. HRQoL was assessed by using the SF‐36 questionnaire. Expanded Disability Status Scale (EDSS) and Beck Depression Inventory (BDI) scale were assessed as variables affecting the HRQoL of MS patients. Results –  EDSS score correlated negatively with all SF‐36 health dimensions, and the highest statistically significant coefficients were for physical functioning (r = −0.682), and social and role functioning (r = −0.407 and −0.405 respectively). BDI correlated statistically significantly negatively (P < 0.01) with all SF‐36 health dimensions. Conclusions –  Our findings suggest that both disability and depression significantly influence the HRQoL in Serbian MS patients, with depressive symptoms having the major influence.