Background: Growth hormone-releasing hormone (GHRH), growth hormone, and insulinlike growth factor 1 have potent effects on brain function, their levels decrease with advancing age, and they likely play a role in the pathogenesis of Alzheimer disease. Previously, we reported favorable cognitive effects of short-term GHRH administration in healthy older adults and provided preliminary evidence to suggest a similar benefit in adults with mild cognitive impairment (MCI). Objective: To examine the effects of GHRH on cognitive function in healthy older adults and in adults with MCI. Design: Randomized,double-blind, placebo-controlledtrial. Setting: Clinical Research Center, University of Washington School of Medicine in Seattle. Participants: A total of 152 adults (66 with MCI) ranging in age from 55 to 87 years (mean age, 68 years); 137 adults (76 healthy participants and 61 participants with MCI) successfully completed the study. Intervention: Participants self-administered daily subcutaneous injections of tesamorelin (Theratechnologies Inc), a stabilized analog of human GHRH (1 mg/d), or placebo 30 minutes before bedtime for 20 weeks. At baseline, at weeks 10 and 20 of treatment, and after a 10-week washout (week 30), blood samples were collected, and parallel versions of a cognitive battery were administered. Before and after the 20-week intervention, participants completed an oral glucose tolerance test and a dual-energy x-ray absorptiometry scan to measure body composition. Main Outcome Measures: Primary cognitive outcomes wereanalyzedusinganalysis ofvarianceandincluded3composites reflecting executive function, verbal memory, and visualmemory. Executive function was assessed with Stroop Color-Word Interference, Task Switching, the Self-Ordered Pointing Test, and Word Fluency, verbal memory was assessed with Story Recall and the Hopkins Verbal Learning Test, andvisualmemorywasassessedwiththeVisual-Spatial Learning Test and Delayed Match-to-Sample. Results: The intent-to-treat analysis indicated a favorable effect of GHRH on cognition (P =.03), which was comparable in adults withMCIandhealthy older adults.Thecompleter analysis showed a similar pattern, with a more robustGHRHeffect (P =.002). Subsequent analyses indicated a positiveGHRHeffectonexecutive function (P =.005)and a trend showing a similar treatment-related benefit in verbalmemory( P =.08). Treatment withGHRHincreased insulinlike growth factor 1 levels by117%(P - .001), which remained within the physiological range, and reduced percentbodyfatby7.4%( P - .001). Treatment withGHRHincreased fasting insulin levelswithinthenormalrangeby35% in adults withMCI(P - .001) but not in healthy adults. Adverse eventsweremildandwerereportedby68%ofGHRHtreated adults and 36% of those who received placebo. Conclusions: Twenty weeks ofGHRHadministration had favorable effects on cognition in both adults with MCI and healthy older adults. Longer-duration treatment trials are needed to further examine the therapeutic potential of GHRH administration on brain health during normal aging and "pathological aging." Trial Registration: clinicaltrials.gov Identifier: NCT00257712.