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BACKGROUND Methotrexate (MTX) is an efficacious treatment for psoriasis; however, its widespread application is limited by its unpredictable efficacy. OBJECTIVES To investigate the association of clinical factors and variants of psoriasis susceptibility genes with clinical responses to MTX in a prospective cohort. METHODS A total of 221 patients with psoriasis were recruited. Patients who achieved Psoriasis Area and Severity Index (PASI) improvement ≥ 75% at week 12 were defined as responders, whereas those with PASI improvement < 50% were defined as nonresponders. In 90 screening patients, genetic variants for 18 single-nucleotide polymorphisms in 14 susceptibility genes, and HLA-Cw6 status were initially compared for responders and nonresponders. Statistically significant associations in genetic variants were verified in all 221 patients. RESULTS Overall, 49% and 45% of patients achieved PASI 75 improvement during screening and verification stages, respectively. Concomitant arthritis with psoriasis and high body mass index (BMI) negatively affect the efficacy of MTX. TT genotype of rs10036748 in TNIP1 was significantly associated with PASI 75 response at week 12 (54% and 37%, P < 0·05). A significantly higher PASI 90 response was observed in patients with TT genotype of rs10036748 (27% vs. 12%, P < 0·01) and TC/TT genotype of rs4112788 in LCE3D (25% vs. 13%, P < 0·05) at week 12 compared with those who had other genotypes. After adjustment for all confounding factors, only BMI (P < 0·05), arthritis (P < 0·05) and genotype of rs10036748 (P < 0·05) were significantly associated with clinical responses to MTX. CONCLUSIONS Patients with psoriasis with TT genotype of rs10036748 in TNIP1, with lower BMI, without arthritis will achieve a better response to MTX.