The aim of the study was to assess the hard tissue response of a composite hydroxyapatite/poly L-lactic acid (HA/PLLA) interference screw for anterior cruciate ligament (ACL) reconstruction compared to a standard PLLA screw. Twelve skeletally mature rams underwent unilateral ACL reconstruction using an autologous bone-patellar tendon graft. Each animal received either two test HA/PLLA interference screws or two control PLLA interference screws. Animals were sacrificed at 6 and 12 months post-implantation and the operated knees excised. Undecalcified sections of the screw and surrounding tissues were cut from resin embedded samples and stained; sections were approximately parallel to the longitudinal axis of the screws. A quantitative assessment of bone formation between each screw type (PLLA vs. HA/PLLA) and adjacent tissue in both the tibia and femur was undertaken using automated image analysis (KS400, Zeiss, UK). The inflammatory response of each screw type was assessed by histological evaluation. New bone formation along the perimeter of the screw threads was statistically significantly higher with the HA/PLLA than the PLLA alone. The inflammatory response as assessed semi-quantitatively by histologically determining the number of inflammatory cells present in the tissue adjacent to the implant, was higher for PLLA than HA/PLLA. Significantly increased new bone formation and decreased inflammatory cells were observed in vivo with the composite screw in comparison with the standard polymer. A novel HA/PLLA composite biomaterial in the form of an interference screw demonstrated an improved hard-tissue response compared to PLLA in a large animal ACL reconstruction. This study determined the differences in the tissue response between PLLA and a composite material of HA/PLLA. The improved tissue related outcomes observed in vivo, may be of benefit clinically in ACL reconstruction.