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Summary: Background: Psoriasis Area and Severity Index (PASI) 90 is suggested to be the new standard endpoint for randomized controlled trials of biologics for psoriasis, whereas treatment guidelines often still refer to PASI 75. Objectives: To analyse in a real‐world setting: firstly, what factors are associated with higher levels of treatment response to biologics; secondly, the health‐related quality of life gains associated with different response levels in clinical practice. Methods: Biologically naïve patients with PASI, Dermatology Life Quality Index (DLQI) and EuroQol (EQ)‐5D outcomes before (maximum 6 months) and after (3–12 months) switch to biologics during registration in the Swedish National Registry for Systemic Treatment of Psoriasis (PsoReg) were included (n = 515). Patient characteristics associated with higher treatment response were analysed by regression analyses. Improvements in absolute PASI, DLQI and EQ‐5D were assessed in different PASI percentage response levels. Results: High PASI percentage response was associated with higher PASI before switch and lower body mass index. DLQI and EQ‐5D improved within all responder groups (P < 0·001). The magnitude of improvements in DLQI (P = 0·02) differed between responder groups. The mean (SD) DLQI improvements for PASI 75<90 responders, PASI 90<100 responders and patients achieving complete skin clearance (PASI 100) were 9·9 (7·4), 11·5 (7·0) and 8·0 (6·1), respectively. Conclusions: PASI percentage change is largely dependent on absolute PASI before switch. Patients in clinical practice lack 'baseline' PASI values as they may switch directly from one treatment to another or stay successfully treated for a longer time period. Treatment goals such as PASI 90 are thus not suitable for treatment guidelines or for follow‐up in clinical practice. What's already known about this topic? Randomized clinical trials of biologics as well as treatment guidelines include treatment goals based on a percentage improvement compared with baseline Psoriasis Area and Severity Index (PASI), such as PASI 75 or PASI 90.Few studies have assessed which factors are associated with high skin clearance rates, or health‐related quality of life (HRQoL) improvements associated with different levels of skin clearance in clinical practice. What does this study add? A high absolute PASI before switch to biologics and low body mass index are associated with higher PASI percentage response.Few patients with baseline PASI >30 achieved complete skin clearance (CSC).All responder groups achieved significant HRQoL improvements.Patients achieving CSC (PASI 100) had lower absolute PASI before switch and lower improvements in absolute PASI and HRQoL than patients with almost cleared skin. What are the clinical implications of this work? Relative measures based on PASI percentage, such as PASI 75 or PASI 90, are not suitable for treatment guidelines or for follow‐up in clinical practice. [ABSTRACT FROM AUTHOR]