This study investigates sex-specific differences in the intestinal microbiota associated with coronary heart disease (CHD) and compares these differences with a non-CVD control group. The research was conducted as part of 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 Quime2 software, the study found that while alpha diversity remained consistent across both sexes, beta diversity showed significant sex-specific variations in the intestinal microbiota. Linear discriminant analysis effect size (LEfSe) analysis revealed sex-centric alterations in the microbiota linked to CHD. Random forest (RF) methodology identified seven bacterial taxa—g_UBA1819 (Ruminococcaceae), g_Bilophila, g_Subdoligranulum, g_Phacoscolarctobacterium, f_Barnesiellaceae, g_Ruminococcus, and an unknown genus from the Ruminococcaceae family—as key discriminators between men and women with CHD. These taxa also emerged as critical discriminators between CHD-afflicted and non-CVD individuals, when analyzed separately by sex. The findings suggest that the dysbiosis of the intestinal microbiota associated with CHD is partially sex-specific, potentially contributing to the sex disparity observed in CVD incidence. Understanding these sex-specific alterations in the gut microbiota could guide the development of effective strategies and therapies aimed at reducing the incidence and recurrence of metabolic and cardiovascular diseases.This study investigates sex-specific differences in the intestinal microbiota associated with coronary heart disease (CHD) and compares these differences with a non-CVD control group. The research was conducted as part of 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 Quime2 software, the study found that while alpha diversity remained consistent across both sexes, beta diversity showed significant sex-specific variations in the intestinal microbiota. Linear discriminant analysis effect size (LEfSe) analysis revealed sex-centric alterations in the microbiota linked to CHD. Random forest (RF) methodology identified seven bacterial taxa—g_UBA1819 (Ruminococcaceae), g_Bilophila, g_Subdoligranulum, g_Phacoscolarctobacterium, f_Barnesiellaceae, g_Ruminococcus, and an unknown genus from the Ruminococcaceae family—as key discriminators between men and women with CHD. These taxa also emerged as critical discriminators between CHD-afflicted and non-CVD individuals, when analyzed separately by sex. The findings suggest that the dysbiosis of the intestinal microbiota associated with CHD is partially sex-specific, potentially contributing to the sex disparity observed in CVD incidence. Understanding these sex-specific alterations in the gut microbiota could guide the development of effective strategies and therapies aimed at reducing the incidence and recurrence of metabolic and cardiovascular diseases.