Differential monocyte subsets are increased in obesity and heart failure (HF). We studied their role as predictors of rehospitalization for HF and their regulation by adipose tissue. Monocyte subsets and body fat composition were determined from 136 patients at the discharge after HF admission. Regulation of monocytes by SAT secretomes from obese/non-obese patients with HF was studied in a cell culture method. Proteomic analysis of secretome SAT was performed by LC-MALDI TOF/TOF. High CD14⁻CD16⁺ monocyte levels indicated less rehospitalization for HF (p = 0.018). SAT secretomes from obese patients increased the CD14⁻CD16⁺monocytes (11.8 ± 5.3 vs 3.9 ± 2.6%; p < 0.01). Differential proteins were determined between obese and non-obese patients with HF. High levels of CD14⁻CD16⁺ monocytes are associated with less rehospitalization for HF. This phenotype is upregulated by SAT secretome from obese patients with HF. This mechanism might help us to understand the obesity paradox in HF.