Importance Necrobiosis lipoidica (NL) is a rare, chronic granulomatous skin disease for which no US Food and Drug Administration (FDA)–approved treatments exist. PCS499, an oral deuterated pentoxifylline analog, may offer therapeutic benefit. Objective To evaluate the safety and exploratory efficacy of PCS499 in adults with biopsy-confirmed NL. Design, Setting, and Participants A phase 2, open-label nonrandomized clinical trial (from January 2019-February 2020) with a 6-month treatment period with an optional 6-month extension was conducted at the University of Pennsylvania and University of Pittsburgh dermatology research centers. Adults aged 18 to 80 years with biopsy-confirmed NL were eligible. Inclusion required a reference lesion of 10 cm 2 or larger and Investigator Global Assessment (IGA) of NL activity score of 2 or greater (scale 0-5). Key exclusions were recent corticosteroid, immunosuppressant, biologic, phototherapy, or pentoxifylline-class use; significant comorbidities; and pregnancy or lactation. Data were analyzed in May 2025. Intervention PCS499, 900 mg, orally twice daily for 6 months, with optional 6-month extension. Main Outcomes and Measures Safety was assessed through adverse event (AE) monitoring, laboratory testing, and electrocardiograms. Exploratory efficacy end points included changes from baseline in IGA, Physician Global Assessments and Patient Global Assessments (PGA, PtGA), NL Color and Ulcer Scale (NLCUS), Dermatology Life Quality Index (DLQI), and Skindex-29 scores. Results Twelve participants were enrolled (median [range] age, 41 [19-66] years; all female individuals; 10 [83%] with diabetes; mean [SD] disease duration, 12.7 [9.3] years), and 10 completed treatment. The most common AE was mild gastrointestinal symptoms (33%). No serious AEs or clinically significant laboratory abnormalities occurred. Participants with ulcerated NL (n = 2 [17%]) achieved complete ulcer closure by day 85 and day 351 without recurrence. Six participants (50%) achieved clear or almost clear IGA status (median [range] time, 111 [54-166] days). Significant improvements were observed in IGA activity (median [IQR] change, −1.5 [−2.0 to 0.0]; P = .03), PGA (median [IQR] change, −1.3 [−2.8 to −0.9]; P = .04), NLCUS inflammation/color (median [IQR] change, −1.0 [−1.8 to 0.0]; P = .02), and induration (median [IQR] change, −1.0 [−2.0 to 0.0]; P = .04), and Skindex-29 function scores (median [IQR] change, −14.6 [−27.1 to 3.1]; P = .05). Conclusions and Relevance This nonrandomized clinical trial found that PCS499 was safe and well tolerated, with evidence of clinical and quality-of-life improvement, particularly in ulcerated NL; however, larger trials are warranted. Trial Registration ClinicalTrials.gov Identifier: NCT03698864