In children, extracorporeal photopheresis (ECP) procedures are often a real challenge as many variables must be considered for safe management of paediatric apheresis. For small children, available information is even more anecdotal. We describe our experience of ECP treatment in children weighing up to 25 kg. From January 1996 to December 2015 a total of 1245 ECP collections were performed in paediatric patients. Among these, 327 ECP collections concerned 19 paediatric patients under 25 kg classified into three body weight groups for data analysis. Cells were collected using a COBE^® Spectra or Spectra Optia separator. Venous access was chosen on a case-by-case basis. Over the years increasingly smaller patients were accepted with similarly smaller volumes collected. We found a significant difference concerning the choice of vascular access in the different groups and patients weighing less than 15 kg had the lowest rates of lymphocyte collection efficiency. No major adverse events were observed, including in children weighing less than 15 kg. Over a 20-year period, ECP has been a safe treatment even in small children, with good tolerance and very few adverse effects. However, its clinical use is sometimes limited by logistical issues such as venous access failure, poor medical condition, severe cytopenia, non-compliance, or long distance from collection centre.