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Background: Chronic pruritus of unknown origin (CPUO) is a highly debilitating disease that lacks effective treatment. There have been case reports of effective use of Janus Kinase (JAK) inhibitors in CPUO, including a case treated with baricitinib, a selective JAK 1/2 inhibitor. Objectives: To evaluate if itch in a cohort of CPUO patients was effectively reduced after treatment with baricitinib. Patients and Methods: This is a retrospective case series examining all patients with CPUO who were treated with baricitinib from February 2022 to August 2023 at the National Skin Center, Singapore. Itch scores on a 0–10 numerical rating scale (NRS) at 0.5‐point intervals were recorded and analyzed over time. Results: Sixteen patients (56% women, mean age of 62.2 ± 19.7 years old) with CPUO were included in the analysis. Their mean [range] duration of chronic itch was 15.4 [1–50] years, and the mean follow‐up period of baricitinib treatment was 10.2 ± 6.7 months. The median [IQR] NRS itch score before and after baricitinib treatment were 8.5 [6.5–10.0] and 3.5 [1.25–5.0], respectively, with a mean reduction in the itch score of 4.9 ± 2.7 (p < 0.0001). All except one patient reported significant improvement in itch severity. There were no reports of symptomatic side effects, except for a drop in hemoglobin in a patient with thalassemia and a dry throat in another patient. There were five cases of mild elevation in creatine kinase levels, three of which normalized over time, and two cases of mild elevation in creatinine levels. Conclusion: This study suggests that baricitinib can effectively reduce pruritus in patients with CPUO and supports the conduct of randomized placebo‐controlled trials to better elucidate the efficacy of JAK inhibitors in management of CPUO. [ABSTRACT FROM AUTHOR]