The global eradication of smallpox and abandonment of mandatory smallpox vaccination has led to an increased proportion of the population who are immunologically naïve to infections caused by Orthopoxviruses (OPV).To present the different courses of OPV infection in children and to highlight the diagnostic difficulties in their differentiation from the other inflammatory processes.We retrospectively evaluated the medical documentation of 5 children with OPV infection. Clinical diagnosis of OPV infection was based on evaluation of animal contact and skin symptoms, characterised by either a single ulcer or disseminated lesions. In all five cases, blood samples and skin swabs were collected from the lesion(s) to identify specific OPV DNA fragments (Vgf, b9R and D11L genes) using PCR.Two children presented with high fever, a single ulcer on the skin and local lymphadenopathy. The three other patients were in good general health and their skin lesions presented as a disseminated vesicular rash. Using the Vgf gene as the target for PCR, OPV infection was confirmed in material collected from skin lesions of all children and in blood samples of 4 children. The B9R and d11L genes tested positive in the skin material of 2 children and blood samples of 2 children. All analysed patients presented a history of ineffective antibiotic therapy.In the case of unclear necrotising skin lesions in children, the primary diagnosis always includes bacterial dermatitis. However, if the patient has come into contact with animals, diagnosis of OPV infection should also be considered.