Abstract Chronic hand dermatitis (CHD) is a common condition with a profound negative effect on patients’ quality of life (QoL) presenting with a wide range of clinical manifestations often involving a combination of erythema, edema, scaling, vesicles and fissuring with intense pruritus and pain. (i) The clinical heterogeneity reflects the complex, multifactorial pathophysiology, with irritant/allergic contact dermatitis and atopic dermatitis as predominant etiological subtypes. (ii) Treatment of CHD remains challenging with no FDA-approved medications; routine treatment options include avoidance of relevant allergens/irritants, emollients, topical corticosteroids, calcineurin inhibitors, phototherapy and systemic immunosuppressive medications. (iii) Providers and patients are often frustrated with unsatisfactory treatment options for CHD. (iv) Topical ruxolitinib, currently FDA-approved for vitiligo and AD, is a Jak1/Jak2 inhibitor that blocks the signaling pathway of several cytokines with a potential to block critical inflammation in CHD. An investigator-initiated, open-label, single-site study (NCT05293717) is currently ongoing to assess the clinical efficacy of 12-weeks treatment with ruxolitinib cream 1.5% in recalcitrant CHD. Here we report the results of an interim analysis after 4 weeks of treatment. This is the first study evaluating the efficacy of ruxolitinib on CHD. This study aims to investigate clinical efficacy and impact on quality of life after 4 weeks of treatment with ruxolitinib 1.5% in moderate-severe CHD. This is an open-label investigator-initiated trial in subjects with recalcitrant CHD. After a washout period, subjects (n = 15, age 18–75) applied ruxolitinib twice daily to the entire hands. Moisturizers were allowed if consistently used before and during the study. Subjects with positive PATCH test that could not avoid the antigen and subjects that reported prolonged contact with water were excluded. Subjects were not permitted to treat skin lesions outside of the hands with prohibited medications or the study drug. Clinical assessments include Investigator Global Assessment (IGA, 5-point scale: clear, almost clear, mild, moderate and severe), Hand Eczema Severity Index (HECSI, a validated scoring system that incorporates both the severity and extent of the disease across fingers, palms, dorsal hands and wrists [5]), Itch Numerical Rating Scale (NRS, average itch over the past 24 h) and change in QoL were assessed with Dermatology Life Quality Index (DLQI). The study drug diary, a prepopulated calendar for each month, records AM/PM drug application and average and worst itch on a scale of 0–10 over the past 24 h. Fourteen subjects (eight female; mean age 50 years) completed the first 4 weeks of treatment. Notably, all the subjects had previously failed topicals (corticosteroid and/or calcineurin inhibitors) and in some cases systemic (e.g. oral steroids, methotrexate and phototherapy) treatments. At baseline, all subjects had an IGA score ≥2 and moderate to severe HECSI score (mean ± SD: 55.7 ± 23.2). The average itch at baseline was moderate (NRS, mean ± SD: 5.5 ± 3.39). After 4 weeks of treatment, 79% of subjects had a ≥2-point reduction in IGA. One hundred percent subjects reached HECSI-50%, and 64% reached a HECSI-75 with a mean reduction in HECSI of 44 (P < 0.01). Seventy-one percent of subjects had a ≥2-point reduction and 57% of subjects had a ≥4-point improvement in average itch (NRS; P < 0.01). Interestingly, 75% of the subjects had a ≥2-point reduction in reported worst daily itch within the first week as noted in their study drug diary. The DLQI was significantly reduced (P < 0.01) in the first month. No treatment-related adverse events were reported, and no rescue medication was needed. Data from 4 weeks interim analysis are encouraging and suggest that ruxolitinib 1.5% may be an effective and well-tolerated treatment for moderate-severe CHD with significant impact on subject’s quality of life. Trial is ongoing to evaluate clinical outcomes at 12 weeks.