Diabetes and hypertension are frequent comorbidities of acromegaly. To analyze the course of diabetes and hypertension at diagnosis and after multimodal therapy in a large cohort of patients with acromegaly. Retrospective study at a tertiary care center. A total of 522 patients with acromegaly treated according to a preestablished protocol. Prevalence of diabetes and hypertension and its relationship with biochemical indices of acromegalic control. The cohort was stratified according to disease activity upon last visit to clinic: (1) surgical remission (n = 122), (2) pharmacologically controlled (n = 92), (3) active disease (n = 148), (4) insulinlike growth factor (IGF)-1 discordance (n = 64), and (5) growth hormone (GH) discordance (n = 96). The prevalence of diabetes and hypertension at diagnosis was 30% and 37%, respectively, and did not change upon the last visit (30.6% and 38%). Both comorbidities were more prevalent at diagnosis and on the last visit than in the general population. Diabetes was less prevalent on the last visit in patients who achieved surgical remission than in those who persisted with active disease (25% vs 40%, P = 0.01). Upon multivariate analysis, diabetes was associated with an IGF-1 at diagnosis >2× upper limit of normal, with the persistence of active acromegaly, the presence of hypertension upon the last visit, with the presence of a macroadenoma, and with female sex. Our findings underscore the importance of an integral approach when managing these patients, focusing not only on the control of GH and IGF-1 levels but also on the timely diagnosis and the specific treatment of each comorbidity.