The present study evaluated the efficacy of a cysteine protease inhibitor (PVS) either alone or combined with Nigella sativa in treatment of cryptosporidiosis in immunosuppressed mice. Seventy two mice were divided equally into eight groups: a normal control group (G1). Other received dexamethasone to induce immunosuppression (G2) acted as a dexamethasone immunosuppressed control. Six immunosuppressed groups were inoculated with infective dose of Cryptosporidum oocycts: (G3) infected control, (G4 & G5) treated with PVS alone in a dose of 50mg/kg & 100mg/kg respectively, (G6 & G7) treated with same dose of PVS and combined with NS 500mg/kg, and (G8) was treated with Paromomycin 250mg/kg. Oocysts shedding were monitored from 2nd to 24th day post-infection. After mice scarification, blood was assessed for hepatorenal drug toxicity. Sections of ileum were subjected to histopathological examination. Mice treated with PVS 100mg/kg combined with NS showed marked improvement with highest significant efficacy (P ≤0.01) diminished oocyst shedding in G6 & G7 by 91% & 94% respectively, versus its efficacy when given alone in G4 & G5 by 83% & 87% respectively or when compared with paromomycin effect in G8 (81%). PVS in different doses showed no toxic effect on hepatorenal parameters.