Background: Microsporidial stromal keratitis poses several diagnostic challenges. Patients may present with corneal ulceration, marked stromal thinning, or even as a quite corneal scar. The presentation of microsporidial stromal keratitis commonly mimics viral keratitis. Microbiology scrapings are usually helpful; however, scraping and culture-negative cases pose a significant diagnostic dilemma. Histopathological examination is diagnostic but shows varying degree of inflammation, predominantly composed of polymorphonuclear leukocytes. Granulomatous inflammation, in microsporidial stromal keratitis, is never well described, and the authors in this article aim to describe the presence of granulomatous inflammation in microsporidial stromal keratitis, in patients with associated herpes... simplex virus (HSV) keratitis. Methods: This was a retrospective and observational study conducted at a tertiary eye care center. Results: Of 263 patients who underwent therapeutic penetrating keratoplasty for infectious keratitis, during 2011–2013, seven patients were diagnosed as microsporidial stromal keratitis. Microsporidial spores could be demonstrated on microbiological scrapings in 5/7 (71%) of cases, but identified on histopathological examination and also confirmed on polymerase chain reaction (PCR) for microsporidium in 100% of cases. There was evidence of diffuse stromal necrosis with markedly severe degree of polymorphonuclear leukocytic infiltrates, with granulomatous inflammation in 42% of cases. Interestingly, these were positive for HSV-1 DNA on PCR. Review of medical records revealed much severe clinical presentations in patients with granulomatous inflammation, in comparison to cases without granulomatous inflammation. Conclusions: The authors hereby recommend that severe clinical presentation in patients with microsporidial stromal keratitis, markedly dense polymorphonuclear leukocytic infiltrates or the presence of granulomatous inflammation on the histopathological examination, should be investigated further for the presence of HSV-1 DNA for better patient management and good visual outcome.