Background Atrial cardiomyopathy (atCM) is an emerging prognostic factor in cardiovascular disease. Fibrotic remodeling, cardiomyocyte hypertrophy, and capillary density are hallmarks of atCM. The contribution of etiological factors and atrial fibrillation (AF) to the development of differential atCM phenotypes has not been quantified. This study aimed to evaluate the association between histological features of atCM and the clinical phenotype. Methods and Results We examined left atrial (LA, n=95) and right atrial (RA, n=76) appendages from a European cohort of patients undergoing cardiac surgery. Quantification of histological atCM features was performed following wheat germ agglutinin/CD31/vimentin staining. The contributions of AF, heart failure, sex, and age to histological characteristics were determined with multiple linear regression models. Persistent AF was associated with increased endomysial fibrosis (LA: +1.13±0.47 μm, P =0.038; RA: +0.94±0.38 μm, P =0.041), whereas total extracellular matrix content was not. Men had larger cardiomyocytes (LA: +1.92±0.72 μm, P <0.001), while women had more endomysial fibrosis (LA: +0.99±0.56 μm, P =0.003). Patients with heart failure showed more endomysial fibrosis (LA: +1.85±0.48 μm, P <0.001) and extracellular matrix content (LA: +3.07±1.29%, P =0.016), and a higher capillary density (LA: +0.13±0.06, P =0.007) and size (LA: +0.46±0.22 μm, P =0.044). Fuzzy k‐means clustering of histological features identified 2 subtypes of atCM: 1 characterized by enhanced endomysial fibrosis (LA: +3.17 μm, P <0.001; RA: +2.86 μm, P <0.001), extracellular matrix content (LA: +3.53%, P <0.001; RA: +6.40%, P <0.001) and fibroblast density (LA: +4.38%, P <0.001), and 1 characterized by cardiomyocyte hypertrophy (LA: +1.16 μm, P =0.008; RA: +2.58 μm, P <0.001). Patients with fibrotic atCM were more frequently female (LA: odds ratio [OR], 1.33, P =0.002; RA: OR, 1.54, P =0.004), with persistent AF (LA: OR, 1.22, P =0.036) or heart failure (LA: OR, 1.62, P <0.001). Hypertrophic features were more common in men (LA: OR=1.33, P =0.002; RA: OR, 1.54, P =0.004). Conclusions Fibrotic atCM is associated with female sex, persistent AF, and heart failure, while hypertrophic features are more common in men.