Introduction Macrophage migration inhibitory factor (MIF) is an important mediator in inflammation and pathogenesis of cardiomyopathy (CMP). We aim to explore any possible association between polymorphisms of MIF genes and CMP in a cohort of Egyptian patients with cardiac dysfunction with or without diabetes mellitus and to investigate the alliance between the identified genotype and their medical features. Patients and methods This is a case-control study where 57 patients with CMP were consecutively admitted to CCU compared with 98 matched healthy controls. Patients were subjected to careful clinical history and physical examination, ECG, routine investigations, and echocardiography. All participants were analyzed for codon -173 G/C polymorphism in MIF genes by using PCR-RFLP methods. Results We found higher Frequency of MIF-173 GG genotype in both diabetic and nondiabetic CMP patients compared to controls (p<0.05). However, we did not find any significant difference in the MIF genotyping between the CMP with or without DM. Conclusion Our results advocate that MIF may have implications for our understanding of the pathophysiology and perturbation in CMP process. We suggested that GG genotype of MIF (-173) gene may be a risk factor for patients with CMP.