COVID-19 is a pandemic disease caused by a coronavirus, designed as SARS CoV-2, whose clinical presentation is widely variable, with most patients having mild or no symptoms, but others developing a malign disease with multi-organ failure and even death. Accumulating data from different populations have shown that obesity is a risk factor for a severe evolution of the disease, however, the mechanisms that explain this association are not clearly understood. An ominous evolution of COVID-19 has been attributed to an exacerbated inflammatory response, designed as "cytokine storm" with augmented production of cytokines/chemokines through the activation of toll-like receptors (TLR) by pathogen-associated molecular patterns, that triggers an inflammatory downstream response, mediated in part by the adaptor molecule, myeloid differentiation factor 88 (MyD88). Previous studies have reported an increased expression of MyD88 and TLRs in people with obesity, mainly in those with metabolic complications. Therefore, we hypothesize, that an underlying increased Myd88/TLR signaling may predispose to patients with obesity to develop an exaggerated and dangerous inflammatory reaction against SARS CoV-2 infection, explaining at least in part, the higher severity of COVID-19. In addition, MyD88/TLR signaling in people with obesity could have a role in the development of several chronic diseases.