To report our first clinical application of a new technique for in situ fenestration of a thoracic stent-graft. After completing a series of in vitro and in vivo experiments, in situ stent-graft fenestration was employed during endograft repair of a saccular thoracic aortic aneurysm in a 77-year-old woman. Because the stent-graft would have covered the left subclavian artery ostium, a modified Zenith TX1 thoracic stent-graft was deployed then fenestrated transluminally using a guidewire followed by serial cutting balloons, which created a fenestration over the LSA sufficiently large to accommodate a Jomed covered stent on an 8-mm balloon. Completion angiography showed exclusion of the aneurysm and brisk flow into the LSA. Following the procedure, the arm pressures were nearly equal. The 6-month CT scan showed no endoleak and a patent subclavian artery stent. In situ graft fenestration to preserve the left subclavian artery after deliberate coverage during endovascular repair of a thoracic aortic aneurysm appears feasible in this initial clinical application. There are uncertainties regarding the long-term stability of the fabric tears that are an inherent part of this technique.