Background and objective: Increasing evidence has shown that treatment with biological therapies reduces the symptoms of plaque psoriasis, with concomitant improvements in health-related quality of life (HRQL). However, these HRQL instruments require evidence supporting their systematic development and psychometric properties to best provide meaningful outcome information. The objectives of this review were to identify and critically appraise patient-reported outcome instruments used in clinical trials of biological agents in patients with psoriasis in the past 10 years, and to evaluate the impact of treatment with biological agents in clinical trials with patients who have moderate-to-severe plaque psoriasis. Methods: Two searches were conducted to identify studies that evaluated patient-reported HRQL outcomes in treatment trials for biological agents in patients with moderate-to-severe psoriasis, and articles that reported on the instrument development process or psychometric properties of measures used to assess HRQL for treatment with biological agents in patients with psoriasis. This evidence was evaluated based on the draft US Food and Drug Administration guidance for labeling claims. Results: The Dermatology Life Quality Index (DLQI) and the Medical Outcomes Study 36-Item Health Survey (SF-36) were identified as the two most frequently used instruments. Statistically significant and clinically meaningful improvements in HRQL were evident during the initial treatment phase using both the DLQI and SF-36, and these improvements were maintained for some time. The DLQI showed greater responsiveness and differentiated most biological agents from placebo across multiple clinical trials, compared with the SF-36. Both instruments demonstrated good psychometric properties, although further research is needed to substantiate minimally important difference estimates for the DLQI and SF-36 in patients with moderate-to-severe plaque psoriasis. Conclusion: The findings of this systematic review indicate that the various biological treatments have a demonstrated impact on disease-specific and generic HRQL outcomes, as well as on clinical efficacy endpoints. The DLQI and SF-36 provide complementary and meaningful information on the impact of biological treatments on HRQL in moderate-to-severe plaque psoriasis. Patients and their physicians can use this information to more comprehensively understand the effects of treatment on patient functioning and wellbeing. Adv Psor Inflam Skin Dis 2009;1(1):7–14.