Rationale: Sirolimus therapy stabilizes lung function and reduces the size of chylous effusions and lymphangioleiomyomas in patients with lymphangioleiomyomatosis.Objectives: To determine whether sirolimus has beneficial effects on lung function, cystic areas, and adjacent lung parenchyma; whether these effects are sustained; and whether sirolimus is well tolerated by patients.Methods: Lung function decline over time, lung volume occupied by cysts (cyst score), and lung tissue texture in the vicinity of the cysts were quantified with a computer-aided diagnosis system in 38 patients. Then we compared cyst scores from the last study on sirolimus with studies done on sirolimus therapy. In 12 patients, we evaluated rates of change in lung function and cyst scores off and on sirolimus.Measurements and Main Results: Sirolimus reduced yearly declines in FEV 1 (22.3 6 0.1 vs. 1.0 6 0.3% predicted; P , 0.001) and diffusing capacity of carbon monoxide (22.6 6 0.1 vs. 0.9 6 0.2% predicted; P , 0.001). Cyst scores 1.2 6 0.8 years (30.5 6 11.9%) and 2.5 6 2 years (29.7 6 12.1%) after initiating sirolimus were not significantly different from pretreatment values (28.4 6 12.5%). In 12 patients followed for 5 years, a significant reduction in rates of yearly decline in FEV 1 (21.4 6 0.2 vs. 0.3 6 0.4% predicted; P = 0.025) was observed. Analyses of 104 computed tomography scans showed a nonsignificant (P = 0.23) reduction in yearly rates of change of cyst scores (1.8 6 0.2 vs. 0.3 6 0.3%; P = 0.23) and lung texture features. Despite adverse events, most patients were able to continue sirolimus therapy.Conclusions: Sirolimus therapy slowed down lung function decline and increase in cystic lesions. Most patients were able to tolerate sirolimus therapy.Keywords: sirolimus; lung cystic destruction; LAM Lymphangioleiomyomatosis (LAM) is a multisystem disease affecting almost exclusively women, which is characterized by cystic lung destruction, renal angiomyolipomas, and lymphangioleiomyomas (1-4). Patients with LAM frequently present with dyspnea on exertion; recurrent pneumothoraces; chylous effusions; incidental detection of lung cysts on imaging studies; and, less frequently, bleeding angiomyolipomas (1, 2). The clinical course of LAM is variable but LAM is generally considered to be a chronic disease with a median transplant-free survival time spanning more than a decade (5). LAM lesions are characterized by proliferation of a neoplastic LAM cell, which has features both of smooth muscle and melanocytic cells (4). The histologic features of LAM consist of cysts and LAM cells in the walls of cysts and along blood vessels, lymphatics, and bronchioles, causing airways narrowing, vascular wall thickening, lymphatic disruption, and venous occlusion (4).The inherited form of LAM associated with tuberous sclerosis complex (TSC) is caused by mutations in the TSC1 or TSC2 suppressor genes (6-8). Sporadic LAM has been associated only with mutations of TSC2 (6-8). TSC1 and TSC2 encode, respectively, hamartin and tuberin, two Corres...