ABSTRACT: Introduction: The pathophysiology and therapeutic options in sepsis-induced lung injury remain elusive. High-dose interleukin 2 therapy (HDIL-2) is an important protocol for advanced malignancies but is limited by systemic inflammation and pulmonary edema that is indistinguishable from sepsis. In preclinical models, IL-2 stimulates angiopoietin 2 (AngP-2) secretion, which increases endothelial permeability and causes pulmonary edema. However, these relationships have not been fully elucidated in humans. Furthermore, the relevance of plasma AngP-2 to organ function is not clear. We hypothesized that plasma AngP-2 concentrations increase during HDIL-2 and are relevant to clinical pathophysiology. Methods: We enrolled 13 subjects with metastatic melanoma or renal cell carcinoma admitted to receive HDIL-2 and collected blood and spirometry data daily. The plasma concentrations of AngP-2 and IL-6 were measured with enzyme-linked immunosorbent assay. Results: At baseline, the mean AngP-2 concentration was 2.5 (SD, 1.0) ng/mL. Angiopoietin 2 concentrations increased during treatment: the mean concentration on the penultimate day was 16.0 (SD, 4.5) ng/mL and increased further to 18.6 (SD, 4.9) ng/mL (P < 0.05 vs. penultimate) during the last day of therapy. The forced expiratory volume in 1 s decreased during treatment. Interestingly, plasma AngP-2 concentrations correlated negatively with forced expiratory volume in 1 s (Spearman r = −0.78, P < 0.0001). Plasma AngP-2 concentrations also correlated with plasma IL-6 concentrations (r = 0.61, P < 0.0001) and Sequential Organ Failure Assessment scores (r = 0.68, P < 0.0001). Conclusions: Plasma AngP-2 concentrations increase during HDIL-2 administration and correlate with pulmonary dysfunction. High-dose IL-2 may serve as a clinical model of sepsis and acute lung injury. Further investigation is warranted.