A new liposomes/chitosan scaffold/human fibrin gel composite system (LCSHFG), as a depot drug delivery system, was developed to deliver low-molecular weight hydrophilic drugs. An antithrombosis drug, Tirofiban, was used as a model drug. Human fibrin gels encapsulated Tirofiban loaded liposomes were formed within chitosan scaffolds to configure the LCSHFG. The in vitro release behaviors of Tirofiban from LCSHFG were studied by characterizing the constituents of LCSHFG. The results show that the release periods of Tirofiban from LCSHFG with 50 microm pores in the chitosan scaffolds are generally 20% or longer more than those with 200 microm pores. The following results were obtained for the system that comprised 50 microm pores. The release periods of Tirofiban from LCSHFG loaded with stearylamine (SA)-liposomes can sustain 20% longer and significantly less burst release (p < 0.01, n = 3) than with liposomes. The release profiles of Tirofiban from LCSHFG change markedly when 0.5 and 2.5% glutaraldehyde is used to cross-link the system. Additionally, for all liposomes, the release periods of Tirofiban from cross-linked LCSHFG with 2.5% glutaraldehyde are 40% or more longer time (e.g., 19 days) with significantly less burst release (p < 0.01, n = 3) than those of noncrosslinked LCSHFG. Notably, the bioactivity of released Tirofiban from LCSHFG that is crosslinked by 2.5% glutaraldehyde effectively inhibits adenosine diphosphate inducing platelet aggregation. The work also suggests that LCSHFG may have potential as a depot drug delivery system for low-molecular-weight hydrophilic drugs.