In this paper, an integrated process based on hydrophilic and hydrophobic ionic liquids is proposed to extract penicillin G frorn its fermentation broth and recover it into fresh water. With the aid of buffer salt, hydrophilic ionic liquids [C(4)mim]BF4(1-butyl-3-i-nethylimidazolium tetrafluoraborate) could form an ionic liquids aqueous two-phase systern (ILATPS) and extract penicillin into the ionic liquids-rich phase of ILATPS, while leaving miscellaneous proteins in the ionic liquids-poor phase. Subsequently, hydrophobic [C(4)mim]PF6(1-butyl-3-methylimidazolium hexafluoraphosphate) is introduced into the ionic liquids-rich phase of ILATPS, which transfers the system into a hydrophobic ionic liquids phase in equilibrium with a water-phase system (HOILWS). The majority of hydrophilic [C(4)mim]BF4 is transferred into the ionic liquids-rich phase of HOILWS, leaving most of the penicillin in the conjugated water phase. In comparison with the butyl acetate/water system or the polymer- aqueous two-phase system, the integrated ionic liquids system shows several advantages: (1) Penicillin is efficiently extracted into the ionic liquids-rich phase at neutral pH, so the protein emulsification met in the organic solvent system is avoided. (2) Hydrophobic ionic liquids could separate hydrophilic ionic liquids away from the penicillin-containing aqueous phase. Consequently, the trouble for recovering the phase-forming material in the polymer- aqueous two-phase system is overcome. Moreover, the experimental results suggest that the partitioning behaviors of penicillin in ILATPS and HOILWS are different. In ILATPS, the logarithm of the partitioning ratio of penicillin (In K) increases proportionally with the concentration difference of ionic liquids between ionic liquids-rich and liquids-poor phases (A[ionic liquids]), and the partitioning ratio exceeds 1000 at A[ionic liquids] = 2.5 mol/L. While in HOILWS, In K decreases monotonically with A[ionic liquids], and more than 90% penicillin could be recovered from the ionic liquids-rich phase of ILATPS when the mole ratio of [C(4)mim]PF6/[C(4)mim]BF4 exceeds 1. Moreover, the partitioning ratio approaches that in the [C(4)mim]PF6/water systern when the [C(4)mim]PF6/[C(4)mim]BF4 ratio in HOILWS is sufficiently large. A modified Flory-Huggins model is proposed to elucidate the partitioning behaviors in the two ionic liquids systems, which emphasizes the key role of energic equilibrium in determining In K ionic liquids solution. In ILATPS, the distance between ionic liquids aggregates is relatively large, which makes the long-range "selfenergy" dominating the partitioning behaviors of penicillin. In contrast, in HOILWS the distance between ionic liquids aggregates is greatly suppressed, which magnifies the entropic loss and hydration repulsion between ionic liquids aggregates and makes them as determinants for the partitioning of penicillin in HOILWS. The conclusions from this model are validated by a series of experimental observations, including the salt's type and concentration, hydrophobic/hydrophilic ionic liquids ratio, and ionic liquids species.