Abstract Background Tofacitinib is an oral Janus kinase inhibitor that is being investigated for psoriasis. Psoriasis impacts on physical and psychological well‐being; improvements in health‐related quality of life ( HRQ oL) with etanercept in psoriasis are well documented. Objective To evaluate HRQ oL with tofacitinib, vs. placebo or etanercept, in the Phase 3, randomized, placebo‐controlled, non‐inferiority, Oral‐treatment Psoriasis Trial ( OPT ) Compare Study ( NCT 01241591). Methods Adults with moderate to severe chronic plaque psoriasis were randomized 3:3:3:1 to tofacitinib 10 or 5 mg twice daily ( BID ), etanercept 50 mg twice weekly or placebo, for 12 weeks. Patient‐reported outcomes ( PRO s) included Dermatology Life Quality Index ( DLQI ), Itch Severity Item and Patient Global Assessment of psoriasis. Results At baseline, 83.4% (911/1092) of patients had a DLQI score ranging between 6 and 30, indicating a substantial burden of disease. By Week 12, 47.3%, 43.6% and 30.9% of patients in the tofacitinib 10 mg BID , etanercept and tofacitinib 5 mg BID groups, respectively, had a DLQI score of 0 or 1 (no effect of psoriasis on QoL) vs. 7.8% for placebo (all P < 0.0001). Tofacitinib significantly reduced itch vs. placebo ( P < 0.05 both doses) and etanercept ( P < 0.0001 both doses) within 1 day of starting treatment. Furthermore, reductions in itch were greater with tofacitinib 10 mg BID , vs. etanercept, at Weeks 2–12 (all time points P < 0.05). At Week 2, an Itch Severity Item score of ‘little or no itch’ was more frequent with tofacitinib 10 mg (68.6%) vs. etanercept (57.4%) and placebo (12.2%), and the Pt GA response rate was significantly greater with tofacitinib 10 mg vs. placebo ( P < 0.05). Conclusion Oral tofacitinib provided significant improvements across multiple PRO s by Week 12. Improvements with tofacitinib 10 mg BID were comparable to etanercept, and improvements in itch were greater and more rapid with tofacitinib 10 mg BID .