Fenretinide, a chemotherapeutic agent for cancer, is water-insoluble and has a very low oral bioavailability. Hence, the objective was to deliver it as an injectable depot and improve the drug solubility and release behavior from poly(lactide-co-glycolide) (PLGA) microspheres by incorporating non-ionic surfactants with fenretinide. Enhancement of drug solubilization was observed with Brij 35 or 98, Tween 20 and Pluronic F127, but not Pluronic F68. Co-incorporation of Brij 98 with fenretinide significantly changed the microsphere morphology improved and fenretinide release profile. The most optimal microspheres formulation, with 20% Brij 98 as excipient, showed an initial in vitro burst around 20% and a sustained release over 28 days in a solubilizing release medium at 37 °C. The effect of addition of MgCO3, drug loading and polymer blending on the release of fenretinide from PLGA microspheres was also investigated and observed to enhance the drug release.