Background:. Most patients with relapsing-remitting multiple sclerosis (RRMS) are initially treated with moderate efficacy disease-modifying therapies (meDMTs), and only a smaller group of highly active patients are initiated on a high efficacy disease-modifying therapy (heDMT). Real-world data have shown that choosing a heDMT as the initial therapy in highly active RRMS patients is more effective than using a meDMT, and that in patients with breakthrough disease on a meDMT escalation of treatment to a heDMT is more effective than staying on the same or switching to another meDMT. The role of age and sex as determinants for selection of the initial treatment intensity, and for using escalation of treatment intensity in patients with relapse activity on treatment with meDMTs, is only partially known. Methods:. We included all Danish patients with RRMS registered in The Danish Multiple Sclerosis Registry who began a DMT since 2014 and stratified the cohort according to sex and age < 40 and ≥ 40 years at first DMT treatment. We studied determinants, with emphasis on age and sex, for the primary choice of therapy, for adherence to the initial therapy and for treatment escalation. Based on existing literature and clinical relevance, we included the following potential confounders in the analyses: DMT efficacy, pre-treatment relapse activity, disease duration, Expanded Disability Status Scale (EDSS) score, and, in a subgroup, MRI activity. Results:. With all covariates mutually adjusted, patient age was a strong decisive factor for choosing a heDMT with odds ratio 1.69 for starting a heDMT in patients < 40 years compared with patients ≥ 40 years. Men had odds ratio 1.53 for starting with a heDMT compared with women. The odds ratio of heDMT in patients with EDSS > 3 vs ≤ 3 was 3.49, and every additional relapse was associated with increased odds ratio 2.33 for heDMT. Patients were more adherent to the initial heDMTs than to the initial meDMTs. Patients above 40 years were more prone to stay on the initial treatment compared to patients below 40, regardless of whether the initial treatment was meDMT (p<0.001) or heDMT (p=0.008) (covariates mutually adjusted). Relapse activity resulted in escalation of therapy to a heDMT in 67% of patients aged < 40 years (N=273) and in 56% patients aged 40 years or above (N=159) (p=0.008), and younger patients had odds ratio 1.46 of escalating therapy compared to older patients. Male patients were more likely to have treatment escalation to heDMTs than female patients (odds ratio 2.03). Conclusion:. Age and sex appear to be independent determinants for the choice of the initial DMT and for the decision of treatment escalation in patients with breakthrough disease on a meDMT. It is unfortunate, if older age is a factor that make choice of a heDMT more unlikely, as many DMTs seems to be less efficacious in older patients.