Background/Objective Ingenol mebutate gel is approved for actinic keratosis field therapy, but little has been published as a treatment of basal cell carcinoma (BCC). Our objective is to characterise the histopathological changes and the infiltrating cell populations to better understand its mechanism of action. Methods Sixteen patients with various BCC subtypes were prospectively evaluated and treated once daily for two consecutive days with ingenol mebutate gel 0.05% under occlusion. Patients were randomised to two arms: the first arm was biopsied between the third and the tenth day after treatment initiation ('early immune response'), and the second arm was biopsied at day 30 after treatment initiation ('late immune response'). The immunopathology was evaluated by immunohistochemistry: anti‐CD3, anti‐CD4, anti‐CD8, anti‐CD20, anti‐CD56, anti‐CD68, anti‐Bcl‐2, anti‐CASP3, anti‐FoxP3, anti‐GrzB and anti‐TIA‐1. Results Ten BCCs were in complete remission after 2 years of follow‐up. The early immune response was characterised by a quick recruitment of T lymphocytes, macrophages and natural killer cells. At later time‐points, T‐regulatory cells and some pro‐apoptotic markers were detected. Treatment‐related adverse events were described. Conclusion Ingenol mebutate gel produces a transient immuno‐inflammatory response and an important necrosis reaction in BCCs. Larger studies will be required to determine the maximum effective tolerated dose of ingenol mebutate gel for BCC.