Introduction <p>Chronic Hand Eczema (CHE) is a multifactorial, burdensome, inflammatory skin disease, with limited treatment options. In a double-blind dose-ranging phase&#xa0;2b clinical trial, participants with CHE received delgocitinib cream, a topical pan-Janus kinase (JAK) inhibitor, or cream vehicle (clinical results published elsewhere). The objectives were to analyse patient-reported outcomes (PROs) in participants with mild and moderate to severe CHE at screening, and to investigate the impact on PROs during treatment in participants with moderate to severe CHE.</p> Methods <p>Firstly, Dermatology Life Quality Index (DLQI), EQ-5D-5L, and Hand Eczema Impact Scale (HEIS) per severity were analysed at screening. Secondly, PROs were analysed in the subset of participants with moderate to severe CHE; participants receiving delgocitinib cream 20&#xa0;mg/g were compared with participants receiving cream vehicle for 16&#xa0;weeks.</p> Results <p>At screening, mean (SD) DLQI, EQ-5D-5L, and HEIS were 8.1 (5.8), 0.788 (0.175), and 1.7 (0.8), respectively for mild CHE (<i>n</i> = 93), and 12.1 (6.9), 0.689 (0.236), and 2.3 (0.9) for participants with moderate to severe CHE (<i>n</i> = 202), respectively. Among the participants with moderate to severe CHE who received delgocitinib (<i>n</i> = 41), the least squares mean [SE] change from baseline to week&#xa0;16 improved compared to cream vehicle (<i>n</i> = 38) in DLQI (− 7.1 [0.9] vs. − 4.6 [0.9]), EQ-5D-5L (0.228 [0.032] vs. 0.096 [0.034]), and HEIS (− 1.5 [0.2] vs. − 0.8 [0.2]) (<i>P</i> &lt; 0.05).</p> Conclusions <p>Mild CHE had a moderate effect, whereas moderate to severe CHE had a very large effect on patients’ Health-Related Quality of Life at screening. Treatment with delgocitinib cream was associated with considerable improvement in PROs and represents a potentially valuable treatment option.</p> Trial Registration <p>ClinicalTrials. gov identifier NCT03683719.</p>