At present, most of the worldwide transformer fleet uses mineral oil as insulation fluid. However, the use of natural ester is playing an increasing role as safer and eco-friendly alternative to mineral oil. From the utilities’ perspective, the change in the mineral oil paradigm can be approached by replacing their assets by new eco-friendly transformers or refurbishing their assets, substituting only the insulating fluid. To make an informed decision, guidelines indicating how a transformer designed for mineral oil would behave when operating with natural ester, are of paramount importance. In the present research, temperature rise tests were carried out in a 15MVA ODAF core-type power transformer, under different operating conditions. Tests were run for mineral oil as insulating fluid and subsequently repeated for natural ester. To gain further insights on experimental results, thermal modelling of the transformer under the same test conditions was carried out, using Thermal-Hydraulic Network Models and Computational Fluid Dynamics techniques. From the present work it was found that the relationship between the thermal behaviour of the transformer using natural ester or mineral oil is not simple as it depends on the operating conditions of the transformer and on the geometry of the windings.