BACKGROUND/OBJECTIVES: In recent years, a possible connection between HLA-Cw6 and a distinctive cardiometabolic (CM) profile in patients with psoriatic disease (PsD) has been proposed, although there is still little support for this. Our aim was to further investigate this possible association by studying a large population of PsD patients. METHODS: For this study, three different cohorts of patients with PsD were analyzed: two with a majority of cutaneous psoriasis, pooled n: 600, and a third with only psoriatic arthritis-PsA-cases, n: 340. Potential relationships between HLA-Cw6 and the different CM risk factors (hypertension, diabetes, obesity, dyslipidemia) were analyzed using univariate and multivariate regression models, while the final net effect was assessed using fixed- or random-effects meta-analyses, as appropriate. RESULTS: In the PsA cohort, no association was detected between HLA-Cw6 carriership and any of the CM comorbidity factors. In psoriasis cohorts, after correcting for age, sex, disease duration, and arthritis, HLA-Cw6 carriers had a reduced diabetes risk (OR 0.49, 95%CI: 0.26-0.91, = 0.026). This latter effect was confirmed by a fixed-effects meta-analysis of the included cohorts (pooled OR: 0.50, 95%CI: 0.27-0.90). CONCLUSIONS: This work demonstrates a potential protective effect of the HLA-Cw6 allele on the risk of diabetes in PsD. Our findings together with those of others seem to confirm the existence of a novel HLA-Cw6-linked cardiometabolic endotype in this disease.