Adalimumab and secukinumab are commonly used for moderate-severe psoriasis vulgaris (PV), but distinct individual response and impaired effectiveness happen occasionally. Little is known about it. Here, we report a proteomic analysis of psoriatic lesions from patients treated with these drugs using Data Independent Acquisition Mass Spectrometry (DIA-MS). Thousands of differentially expressed proteins (DEPs) changed over 12 weeks of treatment. Network analysis showed DEPs could interact and induce transformation in matrix components, metabolic regulation, and immune response. PRM analysis suggested S100s, STAT1, KRT2, TYMP, SOD2, HSP90AB1, TFRC, and COL5A1 were the most significantly changed proteins in both groups. There is a positively association between the psoriasis area and severity index (PASI) score and three proteins (TFRC, IMPDH2, KRT2). Our study suggests that inhibition of IL-17A and TNF-α can induce multiple molecules change in psoriatic lesions and overlapping effect on immune response and proces