This study investigates sex-specific differences in the intestinal microbiota of men and women with coronary heart disease (CHD) compared to non-CVD individuals. The research was conducted within the CORDIOPREV study, involving 837 men and 165 women with CHD, and a reference group of 375 individuals without CVD. Using 16S metagenomics on the Illumina MiSeq platform and Quiime2 software, the study identified sex-specific variations in the intestinal microbiota, with alpha-diversity remaining consistent across both sexes. Linear discriminant analysis effect size (LEfSe) analysis revealed sex-specific alterations in the microbiota linked to CVD. Random forest (RF) analysis identified seven bacterial taxa as key discriminators between men and women with CHD, as well as between CHD and non-CVD individuals. These findings suggest that sex-specific dysbiosis in the intestinal microbiota may contribute to the sex disparity in CVD incidence. The study highlights the importance of considering sex-specific mechanisms in the development of strategies and therapies for metabolic and cardiovascular diseases. The results indicate that the gut microbiota composition varies with sex, potentially explaining the sex-based differences in CVD incidence. The study also found that certain bacterial taxa, such as g_UBA1819, g_Bilophila, and g_Subdoligranulum, were significantly associated with CHD in men and women. The study underscores the need for sex-specific approaches in addressing gut microbiota dysbiosis related to CVD.This study investigates sex-specific differences in the intestinal microbiota of men and women with coronary heart disease (CHD) compared to non-CVD individuals. The research was conducted within the CORDIOPREV study, involving 837 men and 165 women with CHD, and a reference group of 375 individuals without CVD. Using 16S metagenomics on the Illumina MiSeq platform and Quiime2 software, the study identified sex-specific variations in the intestinal microbiota, with alpha-diversity remaining consistent across both sexes. Linear discriminant analysis effect size (LEfSe) analysis revealed sex-specific alterations in the microbiota linked to CVD. Random forest (RF) analysis identified seven bacterial taxa as key discriminators between men and women with CHD, as well as between CHD and non-CVD individuals. These findings suggest that sex-specific dysbiosis in the intestinal microbiota may contribute to the sex disparity in CVD incidence. The study highlights the importance of considering sex-specific mechanisms in the development of strategies and therapies for metabolic and cardiovascular diseases. The results indicate that the gut microbiota composition varies with sex, potentially explaining the sex-based differences in CVD incidence. The study also found that certain bacterial taxa, such as g_UBA1819, g_Bilophila, and g_Subdoligranulum, were significantly associated with CHD in men and women. The study underscores the need for sex-specific approaches in addressing gut microbiota dysbiosis related to CVD.