The important role of the immune system and inflammation in the pathophysiology of heart failure (HF) is becoming increasingly appreciated. We have reviewed the prognostic significance of under-recognized aspects of the leukocyte differential in HF, including lymphocytes, monocytes, eosinophils and mast cells. Studies to date evaluating lymphocyte counts in both chronic and hospitalized HF patients have consistently shown worse prognosis associated with low lymphocyte counts, despite widely heterogeneous study designs. Limited data suggest elevations in monocyte-derived cytokines and serum monocyte count may be predictive of poor outcomes in HF. Further data are required to better define the relationship between eosinophils, mast cells and HF. Leukocyte differentials are widely available, simple, inexpensive and appear to have independent prognostic significance, beyond traditional risk factors. Enhanced sympathetic activation and increased circulating cytokine levels (particularly tumor necrosis factor) have been implicated in the variability of leukocyte subpopulations. To date, immune-modulators targeting these mediators have been largely unsuccessful in improving cardiovascular outcomes in HF. Given the potential role of the immunological axis in HF, there may be an unmet need for novel therapeutic agents that can safely and effectively ameliorate these leukocyte derangements and perhaps improve the unacceptably high event rate in this population. Variations in leukocyte differentials may identify a high-risk subset of patients that may benefit from tailored immune therapies.