The risk factors associated with COVID-19 related severity, morbidity, and mortality, i.e., obesity MESHD obesity HP (often associated with NAFLD), hyperglycemia MESHD hyperglycemia HP, hypertension MESHD hypertension HP and dyslipidemia all cluster together as metabolic syndrome MESHD (MetS). Instead of studying association of these risk factors with COVID-19, it makes sense studying the association between MetS on one hand and COVID-19 on the other. This study explores a molecular basis underpinning the above association. Severity of COVID-19 patients with MetS could be due to functional alterations of host proteins due to their interactions with viral proteins. We collected data from Enrichr (https://amp.pharm.mssm.edu/Enrichr/), DisGeNET (https://www.disgenet.org/) and others and carried out enrichment analysis using Enrichr. Various biological processes and pathways associated with viral protein interacting partners are known to involve in metabolic diseases MESHD. The molecular pathways underlying insulin resistance MESHD insulin resistance HP, insulin signaling and insulin secretion are not only involved in diabetes but also in CVD and obesity MESHD obesity HP (associated with non-alcoholic fatty liver disease MESHD; NAFLD). Lipid metabolism/lipogenesis, fatty acid oxidation and inflammation MESHD are associated with MetS. Viral interacting host proteins are associated and enriched with terms like hyperglycemia MESHD hyperglycemia HP, coronary artery disease MESHD, hypertensive disease MESHD related to CVD and liver diseases MESHD in DisGeNET. Association of viral interacting proteins with disease MESHD-relevant biological processes, pathways and disease MESHD-related terms suggests that altered host protein function following interaction with viral proteins might contribute to frequent occurrence and/or severity of COVID-19 in subjects with MetS. Such analysis not only provides a molecular basis of comorbidity but also incriminates host proteins in viral replication, growth and identifies possible drug targets for intervention.