Multiple Sclerosis (MS) is the most common, primary neurogenic cause of disability among young adults. We investigated demographic and clinical factors associated with unemployment on the example of 150 MS patients receiving immunomodulatory treatment in Poland. This study was based on clinical evaluation and collection of self-reported questionnaires, with an attention to self-motivation, severe fatigue and moderate disability. Patients who were unemployed (40% of all patients) had a mean disease duration of almost 5 years. Older (p<0.001), less educated (p = 0.007) and more severely disabled patients (p<0,001) were most likely to be unemployed. Moderate disability (OR = 11.089 95% CI: 4.11–34.201, p<0,001), severe fatigue (OR = 2.625 95% CI: 1.02–6.901, p = 0,046) and lower level of self-motivation (KNS) (OR = 0.947, 95% CI: 0.896–0.006, p = 0.042) were independently associated with unemployment.