The processing and characterization of biodegradable nanocomposites based on poly(ester-urethane) reinforced with different amounts (0.5, 1 and 3 wt %) of nanosized hydroxyapatite (nHA) are reported. The selected poly(ester-urethane) was synthesized starting from a tri-block copolymer based on poly(ε-caprolactone) (PCL) and poly(l-lactic acid) (PLLA). The nanocomposites were prepared by extrusion and by press molding. Several techniques were applied to investigate the properties of the nanocomposites. Electron microscopy revealed that the poly(ester-urethane) matrix is able to phase separate and that the addition of well-dispersed nanofillers modifies the dimension of the segregated phase. The thermal stability of the PU matrix, regulated by the PLLA block, decreased when low contents of nHA (0.5 and 1 wt %) were added, even if the thermal stability of the PCL-block was increased for each nHA amount. The good mechanical response of the nanocomposites confirmed the absence of agglomerates in the dispersion of the nanofillers in the polymeric matrix. The nHA presence also increased the surface hydrophilicity. Furthermore, rheology measurements, mechanical and thermal tests demonstrated the different behavior induced by the addition of nHA in different amounts. In fact, nHA acts as plasticizer at low concentrations (0.5, 1 wt %) and as reinforcement at a higher nHA amount (3 wt %). In vitro degradation tests were performed using a phosphate buffer solution. The results reported here are relevant for the development of nanocomposites based on a biodegradable and biocompatible polymeric matrix reinforced with small amounts of biocompatible nanofillers for different applications, especially in the biomedical field. ; We are indebted to the Spanish Ministry of Science and Innovation (MICINN) for their economic support of this research (MAT2013-48059-C2-1-R and MAT2014-55778-REDT) as well as the Regional Government of Madrid (S2013/MIT-2862). LP acknowledges also, the support of a JAEDoc grant from CSIC cofinanced by FSE. We thank the technical support of Prof. Juan Lopez Martínez from Universitat Politecnica de Valencia (Spain) for his assistance with water contact angle measurements, as well as Marco Rallini and Franco Dominici from the STM group of the University of Perugia for FE-SEM photographs and microextruder blending, respectively. ; Peer Reviewed