Vascular remodeling (change in vessel diameter) rather than intimal hyperplasia is the most important predictor of luminal loss in immune‐mediated arterial injury, yet little is known about its mechanisms. Here, we show that outward vascular remodeling and intimal thickening, two manifestations of arteriosclerosis with opposing effects on luminal size, result from immune effector mechanisms that are T‐cell dependent and interferon (IFN)‐γ mediated. In our in vivo model of human coronary artery injury by allogeneic peripheral blood mononuclear cells, both processes occur concurrently and are characterized by T‐cell infiltrates with a predominantly IFN‐γ‐producing cytokine profile. Neutralization of IFN‐γ inhibits the arterial and intimal expansion, whereas administration of IFN‐γ enhances these effects. The nonredundant role of IFN‐γ in T‐cell‐dependent remodeling of human coronary arteries demonstrated here presents a new therapeutic target for preservation of vessel lumen in arteriosclerosis.