Macrophage activation syndrome (MAS) is a life-threatening disease with sustained activation of inflammatory cells and release of proinflammatory TNF-α. Under physiological conditions, TNF-α initiates a negative feedback mechanism, mediated by shedded, soluble TNF receptor ectodomains, eventually limiting the inflammatory reaction. Here, we report on a 27-year-old critically ill patient with refractory MAS and an insufficient negative feedback regulation, resulting in an overwhelming inflammatory response. A personalized treatment with soluble TNF receptor etanercept resulted in a durable remission. Further studies are warranted to establish whether the TNF cytokine profile may help to successfully guide patient selection for biological therapies.