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Background and Importance Janus kinase (JAK) inhibitors have expanded treatment options for atopic dermatitis (AD). However, safety concerns necessitate rigorous post-marketing evaluation.Aim and Objectives This study aimed to compare the safety profiles of abrocitinib, baricitinib, tofacitinib, and upadacitinib using adverse event reports (AERs) from the Food and Drug Adverse Event Reporting System (FAERS).Material and Methods Data of JAK inhibitors were collected from the FAERS database covering the period from first quarter of 2004 to the fourth quarter of 2024. Disproportionality signals were detected using the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS). The definition relied on system organ class (SOCs) and preferred terms (PTs) by the Medical Dictionary for Regulatory Activities (MedDRA). And we assessed the temporal distribution patterns.Results We analysed 5,231 JAK inhibitors-related AERs extracted from the FAERS database. Baricitinib was associated with an elevated risk of cardiac disorders (ROR=12.07, 95% CI: 7.4-19.68) and pregnancy-related toxicity (ROR=17.08, 95% CI 6.33-46.1). Upadacitinib showed strong signals related to surgical/procedural events, including therapy interruption (ROR=13.56, 95% CI: 10.56-17.42) and surgery (ROR=4.02, 95% CI: 3.06–5.28). Abrocitinib was characterised by nausea (ROR=5.29; 95% CI 4.01-6.97) and therapeutic product effect incomplete (ROR=20.74; 95% CI 16.87-25.5), while tofacitinib exhibited prominent off-label use signals (ROR=22.94; 95% CI 16.77-31.38). All agents except tofacitinib showed a significantly increased mortality risk. Adverse events (AEs) displayed a distinct biphasic temporal pattern: AER frequency peaked in the initial treatment phase (0-30 days and 31-60 days), and cumulative AEs reached another peak during the mid-to-long-term phase of continuous treatment (181-365 days and >365 days).Conclusion and Relevance JAK inhibitors display distinct organ-specific safety profiles in AD management. This study establishes the first comparative safety framework for personalised JAK inhibitor selection in AD, providing clinicians with a basis for tailoring treatment strategies to individual patients.Conflict of Interest No conflict of interest