IMPORTANCE Therapies that reduce psoriasis symptoms may improve work productivity. OBJECTIVE To assess the effect of ixekizumab therapy on work productivity, measured by the Work Productivity and Activity Impairment-Psoriasis (WPAI-PSO). DESIGN, SETTING, AND PARTICIPANTS Three multicenter, randomized double-blind phase 3 trials conducted during the following periods: December 2011 through August 2014 (UNCOVER-1), May 2012 through April 2015 (UNCOVER-2), and August 2012 through July 2014 (UNCOVER-3). Adult outpatients with moderate-to-severe chronic plaque psoriasis were included. INTERVENTIONS In UNCOVER-1, patients were randomized 1: 1: 1 to subcutaneous placebo or 80 mg ixekizumab every 2 weeks (Q2W) or every 4 weeks (Q4W) for 12 weeks; UNCOVER-2 and UNCOVER-3 also had an etanercept arm (50mg twice weekly). Maintenance of initial ixekizumab response was evaluated in UNCOVER-1 and UNCOVER-2 during a randomized withdrawal period following week 12 through week 60. The WPAI-PSO questionnaire was administered at baseline and week 12 for all patients and at weeks 24, 36, 52, and 60 for patients in UNCOVER-1 and UNCOVER-2. MAIN OUTCOMES AND MEASURES Change in work productivity from baseline as measured by WPAI-PSO scores. RESULTS Across trials, 5101 patients consented; 3866 were randomized (mean [SD] age, UNCOVER-1, 45.7 [12.9] y, 68.1% male; UNCOVER-2: 45.0 [13.0] y, 67.1% male; UNCOVER-3: 45.8 [13.1] y, 68.2% male). At week 12 in UNCOVER-1, the ixekizumab Q4W and ixekizumab Q2W groups showed significantly greater improvements in WPAI-PSO scores (least squares mean change from baseline [SE]) relative to placebo: absenteeism (-3.5 [0.87], P<.001; -2.6 [0.84], P=.003, respectively, vs 0.2 [0.88]), presenteeism (-18.8 [1.28], P <.001; -18.3 [1.24], P <.001, vs 0.5 [1.30]), work productivity loss (-20.6 [1.38], P <.001; -19.8 [1.33], P <.001, vs -0.8 [1.40]), and activity impairment (-24.5 [1.18], P <.001; -25.2 [1.15], P <.001, vs 0.8 [1.18]). Similar results were obtained for UNCOVER-2 and UNCOVER-3, with the exception of absenteeism with ixekizumab Q4W in UNCOVER-2. Additionally, ixekizumab-treated patients showed significantly greater improvements in WPAI-PSO scores vs etanercept-treated patients: UNCOVER-2: presenteeism, work productivity loss, activity impairment (P <.001 both doses), UNCOVER-3: activity impairment (ie, regular activities outside of work) (ixekizumab Q2W; P =.009). Improvements in WPAI-PSO scores at week 12 were sustained to at least week 60. CONCLUSIONS AND RELEVANCE Ixekizumab-treated patients reported short-and long-term improvements in work productivity, which could lead to reduced productivity-related cost burden in patients with psoriasis.