Lipid polymer hybrid nanoparticles (LPHNs) combine the characteristics and beneficial properties of both polymeric nanoparticles and liposomes. The objective of this study was to design and optimize gemcitabine hydrochloride loaded LPHNs based on the central composite design approach. PLGA 50:50/PLGA 65: 35 mass ratio (w/w), soya phosphatidylcholine (SPC)/polymer mass ratio (%, w/w) and amount of DSPE-PEG were chosen as the investigated independent variables. The LPHNs were prepared with modified double emulsion solvent evaporation method and characterized by testing their particle size, encapsulation efficiency, and cumulative release. The composition of optimal formulation was determined as 1,5 (w/w) PLGA 50: 50/PLGA 65: 35 mass ratio, 30% (w/w) SPC/polymer mass ratio and 15 mg DSPE-PEG. The results showed that the optimal formulation gemcitabine hydrochloride loaded LPHNs had encapsulation efficiency of 45,2%, particle size of 237 nm and cumulative release of 62,3% at the end of 24 h. The morphology of LPHNs was found to be spherical by transmission electron microscopy (TEM) observation. Stability studies showed that LPHNs were physically stable until 12 months at 4 degrees C and 9 months at 25 degrees C/60% RH. The results suggest that the LPHNs can be an effective drug delivery system for hydrophilic active pharmaceutical ingredient.