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Background Associations between comorbidity and reduced persistence to disease-modifying therapies (DMTs) in multiple sclerosis (MS) have been identified. Limited information is available regarding the association of comorbidity with safety outcomes. The study objective was to evaluate the association of comorbidities with safety outcomes and persistence.Methods We conducted a two-stage meta-analysis of individual participant data from phase III clinical trials of MS DMTs. Individual comorbidities and comorbidity burden, defined as the sum of all comorbidities (n=15), were examined. Safety outcomes, defined using adverse event (AE) data, were reviewed to identify specific AEs of interest, including infection; treatment-emergent autoimmune disease; cancer; elevated transaminases and lymphopenia. We also examined any early trial discontinuation.Results We included 17 clinical trials representing 16 794 MS participants. Over a 2-year follow-up, the pooled proportion of AEs was 64% (95% CI 59.4% to 68.9%) and the majority were infection AEs. Increasing comorbidity burden was associated with an increased rate of AEs (rate ratio (95% CI) 1: 1.13 (1.09 to 1.17); 2: 1.19 (1.14 to 1.23); ≥3: 1.25 (1.18 to 1.33)) compared with those with no comorbidity. When pooled across trials, early discontinuation affected 17% of participants (95% CI 13.8% to 20.9%). A higher risk of trial discontinuation was associated with higher comorbidity burden (2: 1.23 (1.07 to 1.42); ≥3: 1.19 (1.01 to 1.40)) compared with those with no comorbidity. Psychiatric disorders were associated with trial discontinuation.Conclusions Higher comorbidity burden is associated with increased risk of experiencing safety outcomes and early DMT discontinuation among individuals with MS enrolled in clinical trials of MS-DMTs, highlighting the important role of comorbidities in the safety and persistence of DMTs.