Lipomatous hypertrophy of the atrial septum (LHAS) has been associated with cardiac arrhythmias and is defined as fatty infiltration >2 cm thick in the atrial septum. The clinical and histologic features of surgically excised LHAS have not been previously studied. We studied 11 surgical resections of LHAS and compared them with 13 autopsy cases of LHAS and 24 control autopsy hearts. Of 11 surgical patients, eight were women: patients' mean age was 63 years, and six were described as mildly to overtly obese. Symptoms included congestive heart failure, atrial fibrillation, supraventricular tachycardia, palpitations, syncope, and incidental mass found at surgery. Imaging studies typically revealed a right atrial mass with a mean size of 6 cm (range, 2.5- 10 cm). Multivacuolated fat was more extensive in surgical (p = 0.005) and autopsy (p = 0.009) cases of LHAS than in control hearts. Atypical, hypertrophied myocytes were present in 72% of cases of LHAS compared with 8% of controls (p = 0.0003). In autopsy hearts, histologically abundant multivacuolated fat, heart weight, and body size were independently associated with increased atrial septal thickness. LHAS can be surgically excised, it has a distinctive histologic appearance marked by the presence of abundant multivacuolated fat and hypertrophied myocytes, and it is associated with increased body and cardiac mass.