Background <p>Palmoplantar pustulosis (PPP) is a chronic inflammatory skin disease characterized by recurrent pustules on the palms and soles. Current treatments, including topical medications, phototherapy, and systemic therapies, often show limited efficacy. Upadacitinib (UPA), a selective JAK1 inhibitor, has shown potential in treating neutrophilic dermatoses by modulating cytokine activity.</p> Objective <p>To evaluate the efficacy and safety of UPA compared with acitretin (ACI) in the acute phase of PPP through a prospective cohort study.</p> Methods <p>This study was conducted at the Shanghai Skin Disease Hospital from August 2024 to January 2025. A total of 79 patients with acute PPP were enrolled and randomly assigned to receive UPA (15 mg daily) or ACI (20 mg daily) for 4 weeks. Efficacy was assessed using pustule counts, Palmoplantar Pustulosis Area and Severity Index (PPPASI), and Dermatology Life Quality Index (DLQI). Safety was evaluated by recording adverse events (AEs).</p> Results <p>At week 2, the rate of complete pustule clearance was significantly higher in the UPA group (41.9%) than in the ACI group (10.5%, <i>P</i> = 0.003). By week 4, all patients in the UPA group achieved a pustule count &lt; 30, compared with 63.2% in the ACI group. The UPA group also showed greater reductions in PPPASI and higher response rates for PPPASI 50/75/90. Quality of life improvements, as measured by DLQI, were more pronounced in the UPA group. In terms of safety, UPA had a favorable profile with lower overall AE incidence compared with ACI.</p> Conclusions <p>UPA demonstrated superior efficacy over ACI in rapidly clearing pustules and improving skin lesions and quality of life in acute PPP episodes. The findings suggest that JAK1 inhibition may be a promising therapeutic approach for PPP, warranting further investigation in larger trials.</p> Clinical Trial Registration <p> [<a href="http://www.chictr.org.cn">www.chictr.org.cn</a>], identifier [ChiCTR2000036186].</p>