Abstract Objectives A major challenge faced with the manufacture of liposomes is the high volumes of organic solvents used during manufacturing. Therefore, we have implemented an organic solvent-free production method for drug-loaded liposomes and demonstrated its applicability with both aqueous core-loaded and bilayer-loaded drugs. Methods Liposomes were produced by high shear mixing dry powder lipids with an aqueous buffer, followed by down-sizing using a Microfluidizer processor. Liposomes were purified via tangential flow filtration and characterised in terms of size, polydispersity index, zeta potential and drug loading. Key findings Doxorubicin-loaded PEGylated liposomes can be manufactured using this solvent-free method with particle sizes of 100–110 nm, low polydispersity index (PDI) (<0.2) and high drug loading (97–98%). If required, liposomes can be further down-sized via microfluidic processing without impacting drug loading. Similar results were achieved with non-PEGylated liposomes. With bilayer-loaded amphotericin B liposomes, again liposomes can be prepared within a clinically appropriate size range (100–110 nm in size, low PDI) with high drug loading (98–100%). Conclusions We apply a simple and scalable solvent-free method for the production of both aqueous core or bilayer drug-loaded liposomes.