In the current study, oligo(poly(ethylene glycol) fumarate) (OPF)-based hydrogels were tested for the first time as injectable bone substitute materials. The primary feature of the material design was the incorporation of calcium phosphate (CaP) nanoparticles within the polymeric matrix in order to compare the soft tissue response and bone-forming capacity of plain OPF hydrogels with CaP-enriched OPF hydrogel composites. To that end, pre-set scaffolds were implanted subcutaneously, whereas flowable polymeric precursor solutions were injected in a tibial ablation model in guinea pigs. After 8 weeks of implantation, histological and histomorphometrical evaluation of the subcutaneous scaffolds confirmed the biocompatibility of both types of hydrogels. Nevertheless, OPF hydrogels presented a loose structure, massive cellular infiltration and extensive material degradation compared to OPF-CaP hydrogels that were more compact. Microcomputed tomography and histological and histomorphometrical analyses showed comparable amounts of new trabecular bone in all tibias and some material remnants in the medial and distal regions. Particularly, highly calcified areas were observed in the distal region of OPF-CaP-treated tibias, which indicate a heterogeneous distribution of the mineral phase throughout the hydrogel matrix. This phenomenon can be attributed to either hindered gelation under highly perfused in vivo conditions or a faster degradation rate of the polymeric hydrogel matrix compared to the nanostructured mineral phase, resulting in loss of entrapment of the CaP nanoparticles and subsequent sedimentation.