Background: More work is needed to understand the burden of comorbidities in people with multiple sclerosis (MS). Objective: To assess prevalence of 30 comorbidities and impacts of comorbidities on employment outcomes in a working-aged MS cohort. Methods: Participants were from the Australian MS Longitudinal Study ( n = 929). Information on specific comorbidity was obtained (whether or not each was present, doctor-diagnosed, limited their activities and being treated). Results: Comorbidities most frequently reported to limit activities were osteoarthritis (51%), migraines (40%), anxiety (33%), depression (29%) and allergies (18%). Mean MS-related work productivity loss in past 4 weeks was 1.3 days for those without comorbidities and 2.5 days for those with any comorbidity. The annual population costs of work productivity loss were highest for people with depression, allergies, anxiety, migraines and osteoarthritis. Higher number of comorbidities was associated with more work productivity loss and a higher likelihood of not working. These associations were substantially reduced after adjustment for MS symptom severity. Conclusions: Comorbidities substantially impact employment outcomes and these effects were mainly mediated through MS symptom severity. This suggests that optimal and simultaneous management of comorbidities may be a viable strategy to reduce MS symptom severity, which in turn could improve employment outcomes.