Background and Objective: Psoriasis is a multifactorial, chronic, systemic inflammatory disease. Current evidence suggests that psoriasis is associated with many chronic inflammation-related morbidities, but epidemiological studies on the specific characteristics of the psoriasis comorbidome are still lacking. The aim of the present article is to compare the multi-morbidity profile between patients with and without psoriasis. Methods: In a matched case-control study, we extracted data on 57,228 patients and 125 morbidities from the Clalit Health Services Israeli insurance database. Psoriasis cases were matched with control individuals by sex and age at enrolment. As pre-existing comorbidities we considered all conditions already present in controls at the same age as the matched psoriasis case at the time of their diagnosis. The two-proportion Z-test was used to test for differences in the prevalence of comorbidities between the case and control groups, while logistic regression analyses were run to calculate the odds ratio (OR) for each comorbidity. Results: A higher proportion of psoriasis patients had at least one comorbidity (70% vs. 55% approx.); and half of them had two or more comorbidities, as opposed to one in three controls without psoriasis. Judging from a prevalence analysis, more than one in four psoriasis patients already had hyperlipidemia when their psoriasis was diagnosed, while one in five had hypertension or arthropathy. Behcet’s disease, hereditary neurological disorders, rheumatoid arthritis and hidradenitis suppurativa showed the strongest associations with psoriasis, with estimated ORs ranging between 3.5 and 7. Conclusions: These findings confirmed the association between psoriasis and autoinflammatory or rheumatic diseases. Investigating the psoriasis cormorbidome can help to quantify the real burden of comorbidities in psoriasis patients, and thereby support the development and adoption of personalized treatments to further improve their management.