Background: Multiple sclerosis (MS) is associated with high rates of disability pension and work absence. Little is known about work absence in early MS. The objectives of this study were (1) to assess the prevalence of work absence shortly after MS diagnosis, (2) to explore health-related quality of life (HRQoL) and disease impact in relation to work absence and (3) to investigate demographic and clinical factors that may be associated with high work absence. Methods: Patients with relapsing remitting (RRMS) or primary progressive MS (PPMS) were included shortly after MS diagnosis. We collected data on work absence due to MS in the year prior to inclusion, disability (Expanded Disability Status Scale), relapse rate, fatigue (Neurological Fatigue Index), health-related quality of life (HRQoL, 36-Item Short Form Survey) and disease impact (Multiple Sclerosis Impact Scale). For analysis, patients were divided in 2 groups: low work absence (<1 month) and high work absence (≥1 month). Data was analyzed using backward logistic regression techniques. Results: In total, 90 MS patients participated (80 RRMS, 10 PPMS, mean age = 39.3 years, median disease duration since diagnosis = 0.5 year). Work absence in the year prior to inclusion was reported by 66 patients (73.3%). High work absence of ≥ 1 month was reported by 41 patients (45.6%). Disability, gender, age, disease duration and education did not differ between groups. Patients with high work absence reported a lower HRQoL and higher disease impact compared to patients with low work absence. Backward regression analysis showed that high work absence is associated with being single/not married, fatigue and relapses. The strongest association was found for fatigue (highest fatigue vs. lowest fatigue level: OR total group = 7.8, RRMS = 15.8). In RRMS patients the second-strongest association was relapse rate (≥2 relapses in the past year vs. no relapses: OR 11.1). Conclusion: Prevalence of work absence is high in early MS. Patients with high work absence report a lower HRQoL and a higher disease impact. High work absence is associated with being single/not married, fatigue and relapses. Interventions aimed at fatigue and prevention of relapses may help maintain employment in early MS.