Aliphatic polyester biodegradable microspheres have been extensively studied for controlled and minimally invasive in situ protein delivery. However, they are commonly characterized by protein denaturation via acidic polyester degradation products, whereas their supraphysiologic modulus contributes to the inflammatory response upon implantation. To address these limitations, low-melting-point poly(ε-caprolactone-co-glycolide)-b-poly(ethylene glycol)-b-poly(ε-caprolactone-co-glycolide) (PEG-(PCG) 2 ) copolymers were prepared and characterized for their ability to release bioactive stromalderived factor-1α (SDF-1α) as a representative therapeutic protein. The PEG molecular weight was chosen such that it would be crystalline at room temperature to promote easy handling of the microspheres, whereas the molecular weight and composition of the hydrophobic PCG blocks were adjusted to ensure the polymer was a viscous amorphous liquid at 37 °C. Microspheres prepared from the triblock copolymers completely degraded within 8 weeks in vitro with a minor decrease in microenvironmental pH. A prolonged release of SDF-1α was observed with its bioactivity highly retained after encapsulation and release.