BACKGROUND: Comorbidity is common in people with MS (PwMS) and clinically isolated syndrome (CIS), but research exploring factors associated with comorbidity and impacts on health outcomes in newly diagnosed PwMS and CIS is limited. This study aimed to (1) report the prevalence of medical comorbidities in newly diagnosed PwMS and CIS, (2) explore the relationship between comorbidity and demographic factors, (3) examine the relationship between comorbidities and outcomes one year following diagnosis, accounting for baseline outcomes to assess change over time, and (4) explore if these relationships differ with comorbidity treatment. METHODS: Secondary analysis of data collected from a longitudinal, observational study of adults newly diagnosed with MS or CIS 1 month and 12 months after diagnosis (N = 230). Statistical methods included point biserial, Chi-squared, ANCOVA, and multivariate linear regression. RESULTS: The most common comorbidities within the first year following diagnosis were mental health (32.9 %), vascular (32 %), neurological (22.5 %), and musculoskeletal (9.1 %). Age and race were associated with hypertension and heart trouble, respectively. After one year, mental health comorbidity was associated with higher fatigue scores, musculoskeletal and neurological comorbidity with higher pain interference, and neurological comorbidity with less exercise, after accounting baseline for fatigue, pain interference and exercise. Those with treated neurological conditions had worse pain interference compared to those with untreated conditions. CONCLUSIONS: Mental health, neurological, and musculoskeletal comorbidities were common within the first year following diagnosis, and were associated with worse fatigue and pain, and decreased exercise. Future research should explore how early treatment of comorbidities may impact outcomes and disease progression.