Integrins are adhesion molecules critical for the recruitment of leukocytes from blood into peripheral tissues. However, whether integrins are also involved in leukocyte exit from peripheral tissues via afferent lymphatics to the draining lymph node remains poorly understood. In this article, we show that adhesion by the collagen IV–binding integrin α1β1 unexpectedly inhibited macrophage exit from inflamed skin. We monitored macrophages exiting mouse footpads using a newly developed in situ pulse labeling technique. Blockade of α1β1 integrin or genetic deletion (Itga1−/−) increased macrophage exit efficiency. Chemotaxis assays through collagen IV showed more efficient migration of Itga1−/− macrophages relative to wild type. Given that macrophages are key orchestrators of inflammation, α1β1 integrin adhesion may represent a mechanism for regulating inflammatory responses by controlling macrophage exit or persistence in inflamed tissues.