BACKGROUND AND OBJECTIVES: Gastrointestinal infections are an important cause of morbidity and mortality worldwide. There are a few reports of gastrointestinal double infections in immunocompromised patients. In this study, we retrospectively analyzed double infections identified in gastrointestinal mucosal biopsies in a tertiary care center. MATERIALS AND METHODS: This was a hospital-based, observational, retrospective study that included cases from January 2018 to March 2024. The histomorphology of 6352 endoscopic mucosal biopsies was reviewed for the presence of double infections. These cases were analyzed concerning their clinical scenarios and background comorbidities. RESULTS: The prevalence of gastrointestinal infections was found to be 21.22%, the majority affecting the upper gastrointestinal tract (93.1%). Infections caused by various organisms other than H. pylori, including helminths, protozoa, viruses, mycobacteria, and fungi, were detected in a total of 195 cases. Of all the infections, double infections were detected in 10 cases (0.74%). The most common pathogen in the double infections was cytomegalovirus (CMV), in 70% of the cases; followed by Strongyloides stercoralis found in 40% of the cases. Two patients with disseminated infections developed secondary HLH and died. CONCLUSION: Double infections of the GI tract are rare and are cited in the literature mainly in immunocompromised patients. CMV infection or reactivation, and Strongyloides hyperinfection syndrome, should be suspected in refractory IBD patients, even during the first flare, and is a major cause of mortality in these patients. A high index of clinical suspicion and accurate histopathological diagnosis of these infections can reduce morbidity and mortality in immunocompromised patients.