The effects of salinomycin (SAL) on protective cell-mediated immune (CMI) responses of vaccinated and challenged broiler chicks against hydropericardium syndrome virus (HPSV) and Newcastle disease (NDV) were investigated while comparing 3 reference drugs [levamisole, cyclophosphamide (CYP), and cyclosporine (CYS)]. Peripheral lymphoproliferation, skin hypersensitivity reactions, and the ability of chicks to resist virulent HPSV and virulent NDV challenges were used to determine the effects of drugs on CMI responses in chicks. Salinomycin-medicated chicks showed significant (P < 0.05) stimulation of lymphoproliferation and nonsignificant (P > 0.05) stimulation of skin hypersensitivity reactions compared with untreated control chicks. However, skin thickness and lymphoproliferation of SAL-medicated chicks were significantly greater (P < 0.05) than those of CYP- and CYS-treated chicks. The greatest survival rate was recorded in SAL-medicated chicks compared with immune-suppressed (CYP- and CYS-treated) and untreated control chicks after virulent NDV and virulent HPSV challenges. Thus, it was concluded that SAL had beneficial effects on the CMI responses of broiler chicks against HPSV and NDV.