Context:Adipose tissue macrophages (ATMs) are thought to engulf the remains of dead adipocytes in obesity, potentially resulting in increased intracellular neutral lipid content. Lipid-laden macrophages (foam cells [FCs]) have been described in atherosclerotic lesions and have been proposed to contribute to vascular pathophysiology, which is enhanced in obesity.Objective:The objective of this study was to determine whether a subclass of lipid-laden ATMs (adipose FCs) develop in obesity and to assess whether they may uniquely contribute to obesity-associated morbidity.Setting and Patients:Patients undergoing elective abdominal surgery from the Beer-Sheva (N = 94) and the Leipzig (N = 40) complementary cohorts were recruited. Paired abdominal subcutaneous (SC) and omental (Om) fat biopsy samples were collected and analyzed by histological and flow cytometry-based methods. Functional studies in mice included coculture of ATMs or FCs with adipose tissue.Results:ATM lipid content was increased 3-fold in Om compared with SC fat, particularly in obese persons. FCs could be identified in some patients and were most abundant in Om fat of obese persons, particularly those with intra-abdominal fat distribution. Stepwise multivariate models demonstrated depot differential associations: fasting glucose with SC FCs (β = 0.667, P < .001) and fasting insulin (β = 0.413, P = .006) and total ATM count (β = 0.310, P = .034) with Om FCs in models including age, body mass index, high-density lipoprotein cholesterol, and high-sensitivity C-reactive protein. When cocultured with adipose explants from lean mice, FCs induced attenuated insulin responsiveness compared with adipose explants cocultured with control ATMs with low lipid content.Conclusions:FCs can be identified as an ATM subclass in human SC and Om adipose tissues in 2 independent cohorts, with distinct depot-related associations with clinical parameters. Once formed, they may engage in local cross-talk with adipocytes, contributing to adipose insulin resistance.