Psoriasis and multiple sclerosis (MS) are inflammatory disorders with similarities in genetic risk variants and inflammatory pathways. Limited evidence is available on the relationship between the two diseases. We therefore investigated the risk of incident (new-onset) MS in patients with mild and severe psoriasis, respectively. All Danish citizens aged ≥18 years from January 1, 1997 to December 31, 2011 were identified by linkage of nationwide registries at the individual level. We estimated incidence rate ratios (IRRs) adjusted for age, gender, socio-economic status, smoking, medication, comorbidity, and ultraviolet phototherapy, by Poisson regression. There were 58,628 and 9,952 cases of mild and severe psoriasis, and 9,713 cases of MS, respectively. Incidence rates (IRs) of MS per 10,000 person years for the reference population, mild psoriasis, and severe psoriasis were 1.78, 3.22, and 4.55, respectively. Adjusted IRRs of MS were 1.84 (95% confidence interval [CI] 1.46 to 2.30), and 2.61 (95% CI 1.44 to 4.74) in mild and severe psoriasis, respectively. Similar results were observed when adjustment for family history of MS was included in the analyses. Psoriasis may confer a disease severity-dependent risk of MS. Further studies are warranted to establish the mechanisms underlying this relationship and its potential clinical consequences.Journal of Investigative Dermatology accepted article preview online, 09 September 2015. doi:10.1038/jid.2015.350.