Macrophage activation leading to multi-organ dysfunction/failure has been described in various hematologic disorders like hemophagocytic lympho-histiocytosis (HLH), also known as macrophage activation syndrome (MAS) and macrophage activation like syndrome (MALS). Congestive heart failure (CHF) appears to be an uncommon manifestation of macrophage activation. This novel entity of macrophage activation-associated cytokine-mediated CHF has not been well reported in the medical literature. We report two young female patients with acute CHF secondary to macrophage activation-associated cytokine storm. An extensive diagnostic workup was negative for other etiologies, such as ischemia, myocarditis, or infections. Their clinical, laboratory, and pathologic findings did not meet the diagnostic criteria for hemophagocytic syndrome (HPS)/MAS. However, both had laboratory and pathologic findings which were consistent with macrophage activation and cytokine storm. One patient met criteria for MALS. Therapeutically, our patients were promptly treated with steroids with or without anti-cytokine therapy with rapid restoration of cardiac function. Macrophage activation-induced disease may not always fulfil the diagnostic criteria for the currently known macrophage activation disorders. We suggest that markers of macrophage activation and cytokine levels should be part of the diagnostic workup in patients with otherwise unexplained acute CHF. Additional research is warranted to further elucidate the underlying mechanism of this disorder.