Biological therapies (BTs) indicated for psoriasis are highly effective; however, not all patients obtain good results, and loss of effectiveness is the main reason for switching. Genetic factors may be involved. The objective of this study was to evaluate the influence of single-nucleotide polymorphisms (SNPs) on the drug survival of tumor necrosis factor inhibitors (anti-TNF) medications and ustekinumab (UTK) in patients diagnosed with moderate-to-severe psoriasis. We conducted an ambispective observational cohort study that included 379 lines of treatment with anti-TNF (n= 247) and UTK (132) in 206 white patients from southern Spain and Italy. The genotyping of the 29 functional SNPs was carried out using real-time polymerase chain reaction (PCR) with TaqMan probes. Drug survival was evaluated with Cox regression and Kaplan–Meier curves. The multivariate analysis showed that theHLA-C rs12191877-T (hazard ratio [HR] = 0.560; 95% CI = 0.40–0.78;p= 0.0006) andTNF-1031 (rs1799964-C) (HR = 0.707; 95% CI = 0.50–0.99;p= 0.048) polymorphisms are associated with anti-TNF drug survival, whileTLR5rs5744174-G (HR = 0.589; 95% CI = 0.37–0.92;p= 0.02),CD84rs6427528-GG (HR = 0.557; 95% CI = 0.35–0.88;p= 0.013) andPDE3Ars11045392-T together withSLCO1C1rs3794271-T (HR = 0.508; 95% CI = 0.32–0.79;p= 0.002) are related to UTK survival. The limitations are the sample size and the clustering of anti-TNF drugs; we used a homogeneous cohort of patients from 2 hospitals only. In conclusion, SNPs in theHLA-C,TNF,TLR5,CD84,PDE3A, andSLCO1C1genes may be useful as biomarkers of drug survival of BTs indicated for psoriasis, making it possible to implement personalized medicine that will reduce financial healthcare costs, facilitate medical decision-making and improve patient quality of life. However, further pharmacogenetic studies need to be conducted to confirm these associations.