8,695 MS patients were compared with 86,934 non-MS patients (female, 71%; median age, 41). Prediagnosis, MS patients had increased prevalences (P<0.05) of depression (22.7% vs 16.4%), other psychiatric diagnoses (9.8% vs 6.7%), asthma (4.5% vs 3.7%), fracture (4.3% vs 3.5%), suicidal behaviors (1.3% vs 0.9%), epilepsy (0.8% vs 0.4%), and infection incidence the year before diagnosis/match (46.5% vs 38.3%); more used antibiotics (46.6% vs 35.1%), antidepressants (28.4% vs 16.7%), antihypertensives (24.0% vs 19.1%), proton pump inhibitors (15.9% vs 12.1%), anti-asthmatics (10.5% vs 8.4%), antipsychotics (3.1% vs 1.6%), antiplatelets (1.8% vs 0.9%), antiepileptics (1.7% vs 0.6%), and symptomatic treatments. Postdiagnosis (median, 7 years), MS patients had increased comorbidities (incidence rate ratio (IRR) [95% CI]): epilepsy (4.90 [4.17-5.73]), spasticity (4.86 [4.68-5.05]), neuropathy (3.78 [3.55-4.03]), treated depression (3.12 [2.98-3.27]), venous thromboembolism (2.54 [2.14-3.0]), peripheral vascular disease (2.49 [1.89-3.25]), hospitalized infection (2.43 [2.23-2.63]), retinal edema (2.19 [1.31-3.50]), myocardial infarction (2.11 [1.56-2.80]), major cardiac event (2.09 [1.70-2.55]), bowel dysfunction (2.05 [1.91-2.20]), suicidal behavior (1.97 [1.73-2.24]), osteoporosis (1.86 [1.65-2.10]), fracture (1.80 [1.66-1.95]), nondepressive psychiatric disorder (1.75 [1.64-1.85]), any herpes virus (1.48 [1.39-1.57]), opportunistic infection (1.50 [1.44-1.56]), asthma (1.40 [1.26-1.56]). Cancer IRR was similar between groups (1.18 [1.05-1.32]).