AbstractHuman pythiosis is a rarely encountered yet potentially harmful infectious disease. It is mostly caused by Pythium insidiosum, an aquatic fungal‐like organism, and primarily manifests in tropical locales such as India and Thailand. Cutaneous/subcutaneous pythiosis accounts for a small proportion of all clinical forms. The relationship between cutaneous pythiosis and hemoglobinopathy remains uncertain, unlike the vascular form. The histopathology of the disease demonstrates eosinophilic granulomatous inflammation and dense eosinophilic material enveloping the organism, known as the Splendore–Hoeppli phenomenon. These histopathologic characteristics resemble those observed in entomophthoromycosis. Until now, the histopathology of human cutaneous pythiosis has been scarcely delineated in the literature. Herein, we report a case of cutaneous pythiosis in an adult thalassemic agricultural worker who presented with a 2‐month history of a progressive, painful, erythematous infiltrative plaque on the left leg. The definitive diagnosis was ascertained through histopathologic examination and the identification of anti‐P. insidiosum antibodies in the serum utilizing enzyme‐linked immunosorbent assay. This report demonstrates the exquisite histopathologic findings of a rare case of human cutaneous pythiosis.