Acromegaly is usually due to the excessive secretion of GH by a pituitary adenoma. It is frequently accompanied by comorbidities that compromise quality of life and results in elevated mortality rates. To evaluate mortality and morbidity in patients with acromegaly receiving multimodal care. Tertiary care center. Retrospective evaluation of 442 patients (65.4% women; mean age, 43.5 ± 13.1 y) followed for a median of 6 years (interquartile range [IQR], 3-10). Twenty-two patients died during the study period (4.9%), representing a total standardized mortality ratio (SMR) of 0.72 (95% confidence interval [CI], 0.41-1.03). Standardized mortality ratios were 1.5 and 0.44 for patients whose last GH was above and below 2.5 ng/mL, respectively; 1.17 and 0.16 for those whose last GH was above and below 1 ng/mL, respectively; and 0.94 and 0.46 for those whose last IGF-1 was above and below 1.2 times the upper limit of normal (ULN), respectively. The prevalence of diabetes mellitus, hypertension, heart disease, and cancer was 30%, 35%, 8%, and 4.7%, respectively. The most common cause of death was cancer. On multivariate analysis, diabetes, heart disease, and cancer were related to a baseline GH > 10 ng/mL; the presence of cancer and the last IGF-1 were significant predictors of mortality. Survival decreased as the latest GH levels increased from < 1 ng/mL to > 5 ng/mL and as IGF-1 increased from < 1.2 to > 2 times the ULN. Mortality in acromegaly can be successfully reduced, provided patients are treated using a multimodal approach with careful management of comorbidities.