Poly(ethyleneglycol) 500 dimethylether (PEG500DME) was tested as a novel solvent for the manufacture of an injectable in situ forming depot (ISFD) containing poly(D,L-lactide-co-glycolide) (PLGA). The sustained release of pasireotide from the ISFD was evaluated in vitro and in vivo. Furthermore, the local tolerability of the delivery system using PEG500DME was investigated in subcutaneous (s.c.) tissue over 48 days. A flow-through cell was used to determine the in vitro drug release from the ISFD in comparison to a peptide suspension without polymer. The biocompatibility as well as the pharmacokinetic profile of the ISFD was investigated in rabbits. A prolonged peptide release over at least 48 days with an initial burst lower than 1% was observed in vitro for the ISFD compared to the suspension without polymer. A similar tissue response as it was observed for other common PLGA delivery systems was found upon histopathological examination of tissue from the administration site in rabbits. A sustained release of at least 48 days in vivo confirmed the in vitro observation including the low initial plasma concentration levels. Two ISFDs with different peptide loads were used to correlate the in vitro and in vivo data (IVIVC). Overall, the functionality of the ISFD containing PEG500DME as a novel solvent was demonstrated in vitro and in vivo. In addition, the local tolerability of the system confirmed the biocompatibility of PEG500DME in parenteral depots.