Abstract Skeletal defects reconstruction, using custom-made substitutes, represents a valid solution to replacing lost and damaged anatomical bone structures, renew their original function, and at the same time, restore the original aesthetic aspect. Rapid prototyping (RP) techniques allow the construction of complex physical models based on 3D clinical images. However, RP machines usually work with synthetic polymers; therefore, producing custom-made scaffolds using a biocompatible material directly by RP is an exciting challenge. The aim of the present work is to investigate the potentiality of 3D printing as a manufacturing method to produce an osteogenic hydroxyapatite-polylactic acid bone graft substitute.