The current study aims to develop in-situ forming implants (ISFI) of anti-psychotic risperidone to customize schizophrenia therapy. Non-adherence to treatment is the most prevalent unsuccessful clinical outcome in schizophrenic patients. Poly(lactic-co-glycolic acid) (PLGA) was utilized to prepare ISFI using various solvents having different drug solubilization capacity. 33 Box-Behnken Design (BBD) was used to study the effects of independent variables; lactide concentration (A), solvent type (B) and solvent/polymer ratio (S/P) (C) on burst release after 6h (Y1), cumulative release after 40 days (Y2) and injectability time (Y3). Statistical analysis was followed by optimization process to minimize burst release and injectability time with targeted cumulative release to 50% at 40 days. BBD results represented the critical impacts of increasing lactide and PLGA concentrations on reducing drug burst and percent release. Rapid ISFI solidification using DMSO supported the high dispersed drug encapsulation and sustained release. Triacetin demonstrated a lag time between formulation injection and solidification that negatively affected the studied responses. The optimized formulation manifested burst (8.1%), cumulative release (51.08%) and 18 s for injection by mixing PLGA (75:25) and DMSO (S/P = 2.851). Compared with injectable commercial microspheres, ISFI emphasized their potential to enhance compliance and eliminate costs issues of additional oral therapy.