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Objective Cognitive effects in acromegaly patients are poorly understood and the mechanisms involved are still unclear. The aim of this study was to evaluate the cognitive function, depression, and quality of life of acromegaly patients treated with pegvisomant versus somatostatin analogues (SRLs) and to analyze the effect of the different treatments on cognition and possible structural brain changes. Methods This cross-sectional study involved 23 acromegaly patients divided into two groups according to treatment modality: One group of 9 patients treated with pegvisomant and another group of 14 patients treated with SRLs. All participants underwent blood analysis, neuropsychological tests, depression tests, quality of life assessment, and 3-Tesla magnetic resonance imaging. Results We found no significant differences between groups in the neuropsychological tests, depression or quality of life; nor in the whole-brain cortical thickness. In the SRL group, the volume of the thalamus correlated positively with executive function, a correlation not found in the pegvisomant group. In addition, the pegvisomant group had significantly higher levels of insulin than the SRL group. Conclusions In conclusion, in this pilot study, the type of pharmacological treatment in patients with acromegaly and good glycemic control did not influence the cognitive function and cortical brain thickness. However, pegvisomant could play a neuroprotective role on the thalamus that will have to be demonstrated with larger samples in future studies.