OBJECTIVES: The aim of this pre-clinical study was to evaluate the biological performance of two injectable calcium phosphate cement (CPC) composite materials containing poly(D,L-lactic-co-glycolic)acid (PLGA) microspheres with different properties in a maxillary sinus floor elevation model in sheep. MATERIALS AND METHODS: PLGA microspheres were made of either low molecular weight (~17 kDa) acid-terminated PLGA (PLGA(L-AT) ) or high molecular weight (~44 kDa) end-capped PLGA (PLGA(H-EC) ) and incorporated in CPC. Eight female Swifter sheep underwent a bilateral maxillary sinus floor elevation procedure via an extra-oral approach. All animals received both materials, alternately injected in the left and right sinus (split-mouth model) and a time point of 12 weeks was used. Analysis of biological performance was based on histology, histomorphometry, and evaluation of sequential fluorochrome labeling. RESULTS: Both types of CPC-PLGA composites showed biocompatibility and direct bone-cement contact. CPC-PLGA(L-AT) showed a significantly higher degradation distance compared to CPC-PLGA(H-EC) (1949 +/- 1295 mum vs. 459 +/- 267 mum; P = 0.0107). Further, CPC-PLGA(L-AT) showed significantly more bone in the region of interest (26.4 +/- 10.5% vs. 8.6 +/- 3.9% for PLGA(H-EC) ; P = 0.0009) and significantly less remaining CPC material (61.2 +/- 17.7% vs. 81.9 +/- 10.9% for PLGA(H-EC) ; P = 0.0192). CONCLUSIONS: Both CPC-PLGA(L-AT) and CPC-PLGA(H-EC) demonstrated to be safe materials for sinus floor elevation procedures in a large animal model, presenting biocompatibility and direct bone contact. In view of material performance, CPC-PLGA(L-AT) showed significantly faster degradation and a significantly higher amount of newly formed bone compared to CPC-PLGA(H-EC) .