To address the lack of studies on the impact of gender and psychiatric comorbidities on alcohol dependence (AD) and quality of life (QoL), we conducted a cross-sectional study. We compared QoL between 328 men and 86 women with AD, and 215 healthy men and 120 women. Additionally, we examined the association of alcohol-related variables and psychiatric comorbidity with the QoL of men and women with AD while controlling for sociodemographic variables. A structured clinical interview for sociodemographic and alcohol-related variables, Mini International Neuropsychiatric Interview (M.I.N.I.), and World Health Organization QoL (WHOQoL)-BREF scale, was applied. QoL was poorer for AD subjects compared to healthy controls, with no gender differences. Regression analysis showed that the number of hospitalizations and AD with personality disorder predicted poorer QoL for men, whereas AD with depression predicted poorer social relationships for women. These findings suggest the need for gender-differentiated treatment.