Objective To study the impact of secondary mental disorders in patients affected with acromegaly and correlate them with quality of life (QoL) and disease status. Design An observational transversal descriptive and comparative study that evaluates QoL's impact due to secondary mental disorders in affected Mexicans with acromegaly using AcroQoL and SF‐36 instruments. Correlation of the results with the disease's biochemical status was performed. According to Beck's scales, anxiety and depression analyses evaluate QoL's impact, and its gender variability is described. Results Eighty‐five patients with diagnoses of acromegaly were included. The mean age was 43.18 years, 47 being women (55.29%). The mean age at diagnosis was 37.95 years, with no difference between men and women. AcroQoL and SF‐36 global and sub‐domain scores differed significantly between men and women, the latter having lower global and individual sub‐domain scores. The mean score of QoL, according to AcroQoL, is 59.40. In women, the mean values are less (55.13) than men (64.68), p = 0.021. The sub‐domain analyses’ scores in physical, appearance and social relationships were less in women (53.21; 47.34; 62.32) than men (62.68; 56.76; 73.87) p = 0.044, 0.069 and 0.013, respectively. Higher Beck's Depression Inventory (BDI) and Beck's Anxiety Inventory (BAI) scores correlated with lower QoL as assessed by global and individual sub‐domain scores. Women presented significantly higher BDI and BAI mean scores when compared to men regardless of their biochemical status. Anxiety (p = 0.027) and depression (p < 0.001) severity were higher in women compared to men. Conclusion Correlations between female gender, depression/anxiety scores and QoL require further validation. There is much to be routinely done to improve secondary psychopathology in patients affected by this disease. The need for mental status screening at diagnosis should be emphasized to identify secondary mental illnesses to improve QoL with its treatment.