The commonly used antileishmanial drugs are sodium antimony gluconate (SAG), amphotericin B, miltefosine and paromomycin. There are a number of reports that antileishmanial drugs show immunomodulatory properties. Here, we attempt to understand how the innate arm of the immune system is modulated in response to these antileishmanial drugs.BALB/c peritoneal macrophages were treated with miltefosine, SAG, amphotericin B or paromomycin. The membrane fluidity of macrophages following drug treatment was studied in terms of fluorescence anisotropy. The T cell-stimulating ability, production of cytokines and nitrogen and oxygen metabolite production in drug-treated macrophages were also studied. The study was also carried out using peritoneal macrophages from drug-treated BALB/c mice.The antileishmanial drugs altered macrophage membrane fluidity, except amphotericin B. The drug-treated macrophages showed enhanced T cell-stimulating ability and generation of reactive oxygen species, nitrite, interleukin-12 and tumour necrosis factor-α.Antileishmanial drugs can stimulate the innate arm of the immune system, which may have a significant bearing on the cellular arm of the immune system.