Context. Recent clinical trials of intramuscular testosterone in eugonadal men suggest positive effects on verbal memory, but other studies find no effect.

Objective. To determine whether supraphysiological testosterone influences verbal memory and brain function during a verbal memory task in healthy eugonadal older men.

Design. Randomized, double-blind, placebo-controlled crossover trial involving 9 months of participation per participant.

Setting. Hospital-based research facility.

Patients. Fifteen cognitively normal men, aged 66 to 86 years.

Intervention. Testosterone enanthate (200 mg IM every other week for 90 days) crossed over with placebo (sesame oil vehicle IM) with a 90-day washout between treatments.

Main Outcome Measures. Performance on a standardized verbal memory test and brain activity (relative glucose metabolic rates) in medial temporal and frontal regions measured with positron emission tomography during a verbal memory task.

Results. Treatment increased total testosterone by 241%. Behavioral results showed a significant decrease in short delay verbal memory with treatment (p < .05, effect size = 0.59 standard deviation) and a nonsignificant decrease on a composite verbal memory measure (p = .09, effect size = 0.48 standard deviation). PET scans revealed decreased relative activity in ventromedial temporal cortex, (i.e., right amygdala/entorhinal cortex) and increased relative activity in bilateral prefrontal cortex with treatment.

Conclusions. Decreased verbal memory and altered relative activity in medial temporal and prefrontal regions suggests possible detrimental effects of supraphysiological testosterone supplementation in elderly men. The results do not rule out potential benefits with other regimens, cognitive tests, or populations.