Psoriasis is clinically heterogeneous, and symptoms can vary from mild almost cosmetic symptoms to severe disease requiring systemic therapy. Biomarkers predicting disease development are lacking. Herein we explored the genetic background in two polarized cohorts of carefully phenotyped patients with long-term follow-up: consistent mild phenotype (n=696) and severe disease course requiring systemic therapy (n=715). All patients were treated at the same dermatology department ensuring homogenous assessment. Genotyping included known psoriasis-associated variants, with special focus on the IL-23 and NF-κB pathways. A case-case study comparing severe and mild psoriasis phenotypes, controlling for age at disease onset and gender, revealed significant differences between the two groups for SNPs in IL23R, NFKB1, IL21, IL12B, NFKBIL1 and IL23A. HLA-C*06 associated equally in the mild and severe disease cohorts. Strong additive effects when combining HLA-C*06 with IL23A, IL23R, IL12B, NFKB1 or TNIP1 were restricted to the severe cohort, indicating that activation of these pathways may influence disease severity in psoriasis. No protective gene was identified in the mild cohort, suggesting that current screens have primarily identified psoriasis variants associated with a more severe phenotype. These results demonstrate the importance of careful phenotyping and long-term clinical follow-up in genetic studies.