The objective of this study was to investigate the potential of various formulation strategies to achieve 1-month continuous (improved) release of the novel anti-cancer drug, 2-methoxyestradiol (2-ME), from injectable cylindrical poly(DL-lactide-co-glycolide) (PLGA) implants. PLGA implants were prepared by a solvent extrusion method. PLGA 50:50 (M(w)=51 kDa, end group=lauryl ester) (PLGA-lauryl ester) implants loaded with 3-30 wt% 2-ME exhibited a pronounced lag phase (i.e., corresponding to induction time to polymer mass loss) and triphasic release profile. Incorporation of 5 wt% hydroxypropyl-beta-cyclodextrin (HP-beta-CD) (approximately 57% release after 28 days) or Pluronic F127 (approximately 42% release after 28 days) in PLGA-lauryl ester implants reduced the lag-phase and improved the drug release moderately over a period of 28 days. The formation and the incorporation of a 2-ME/polyethylene glycol (PEG) 8000 solid dispersion in PLGA-lauryl ester implants further increased drug release (approximately 21% and 73% release after 1 and 28 days, respectively), attributable to improved drug solubility/dissolution, higher matrix porosity, and accelerated polymer degradation. Blending of PLGA 50:50 (M(w)=24 kDa, end group=COOH) (PLGA-COOH) with the PLGA-lauryl ester also provided moderate enhancement of 2-ME release over a period of 28 days. PLGA-COOH (M(w)=24 kDa) implants with 3-5% w/w pore-forming MgCO(3) exhibited the most desirable drug release among all the formulations tested, and, demonstrated 1-month slow and continuous in vitro release of approximately 80% 2-ME after a minimal initial burst. Hence, these formulation approaches provide several possible avenues to improve release rates of the hydrophobic drug, 2-ME, from PLGA for future application in regional anti-cancer therapy.