Abstract Background Multiple sclerosis (MS) is characterized by demyelination and variable symptomatology, and typically appears during young adulthood, making it a condition of considerable public health concern. Given its chronic nature, understanding of the illness perception plays a crucial role in long-term disease management. Our research aims to examine the factors affecting illness perception among people with MS. Methods The study sample consisted of 166 patients with MS (75.3% women; mean age: 40.9±11.3 years; mean disease duration: 11.6±7.1 years). People with MS underwent medical examination to assess their functional disability measured by Expanded Disability Status Scale (EDSS), and structured interview, during which data on age, sex, education, employment status, income and disease duration were obtained. Finally, they were asked to fill in the Brief Illness Perception Questionnaire (BIPQ), and the Rosenberg Self-esteem Scale (RSE). Data were analysed with multiple linear regression analysis. Results Our results showed an association between functional disability and illness perception (β = 0.22; p < 0.05). However, this association lost its significance upon adding self-esteem into the model (β=-0.53; p < 0.001), with overall explained variance in illness perception rising from 2.7% to 27.5%. No statistically significant contribution of other socio-demographic or clinical variables was observed. Conclusions Higher self-esteem in people with MS appears to be intricately connected to their illness perception. Given that the management of chronic conditions heavily relies on patients’ personal resources, healthcare providers could play a crucial role in fostering self-esteem. By encouraging the development of self-esteem, patients may come to view their illness as more manageable and less daunting, potentially leading to mitigation of negative consequences of functional disability. [Grant support: VEGA 1/0608/23] Key messages • Self-esteem may be stronger predictor of illness perception than functional disability in people with MS. • MS patients may benefit from psychological support aimed at promoting self-esteem.