Objective— Studies suggest the implication of CD16 ⁺ subpopulations (CD14 ⁺ CD16 ⁺ , CD14 ^dim CD16 ⁺ ) in inflammatory diseases. We aimed to determine the frequency of these subpopulations during weight loss in obesity and diabetes, conditions associated with changes in systemic inflammation, and we tested the link with subclinical atherosclerosis. Methods and Results— CD14 ^dim CD16 ⁺ and CD14 ⁺ CD16 ⁺ frequencies were measured by flow cytometry in lean subjects, obese subjects before and after a hypocaloric diet or gastric surgery, and obese diabetic subjects before and after gastric surgery. Both monocyte subsets were increased in obese subjects, with a significant enrichment of the CD14 ^dim CD16 ⁺ subpopulation in obese diabetic patients. Multivariate analysis demonstrated a link between the percentages of CD14 ^dim CD16 ⁺ monocytes and glycemia, independent of fat mass. Drastic weight loss led to a sharp decrease of this subset, the variations of which were strongly related to fat mass changes. A reduction of at least 5% of fat mass was sufficient to observe a significant decrease of CD14 ^dim CD16 ⁺ monocytes. A diminution of the CD14 ⁺ CD16 ⁺ subset was also observed during weight loss and was associated with a decrease in intima-media thickness. Conclusion— This work demonstrates a major impact of fat mass variations on CD14 ^dim CD16 ⁺ monocyte subsets and that the decrease in the CD14 ⁺ CD16 ⁺ subpopulation is linked to a reduction of subclinical atherosclerosis. Clinical Trial Registration— URL: http://clinicaltrials.gov . Unique identifier: NCT00476658.