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Abstract Background There is an unmet need for antithrombotic treatments for venous thromboembolic disease that do not increase bleeding risk. Selectins are cell adhesion molecules that augment thrombosis by activating immune cells to initiate the coagulation cascade. GMI‐1271, a potent small‐molecule E‐selectin antagonist, has been shown in mouse models to decrease thrombus burden with a low risk of bleeding. Methods A first‐in‐human study of GMI‐1271 was conducted to assess its safety, tolerability, and pharmacokinetic (PK) profile. As a secondary end point, biomarkers of coagulation, cell adhesion, and leukocyte/platelet activation were evaluated. Aims 1 and 2 were performed in healthy volunteers and evaluated single and multiple doses of the study drug, respectively. Aim 3 included 2 patients with isolated calf‐level deep vein thrombosis (DVT). Results GMI‐1271 showed consistent PK parameters for doses ranging from 2 to 40 mg/kg. Plasma levels increased in a linear manner with respect to dose, while clearance, volume of distribution, and half‐life were not dose dependent. No accumulation was seen with multiple consecutive doses. No serious adverse events (grade 3 or 4) were reported. Biomarker analysis demonstrated a trend in reduction of soluble E‐selectin (sEsel) levels with GMI‐1271 exposure, while exposure did not impact laboratory testing of coagulation. Two patients with calf vein DVT were treated with GMI‐1271 and demonstrated rapid improvement of symptoms after 48 hours, with repeat ultrasound showing signs of clot resolution. Conclusions We demonstrate that GMI‐1271 is safe in healthy volunteers and provide proof of concept that an E‐selectin antagonist is a potential therapeutic approach to treat venous thrombosis.