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Objectives: To evaluate the in vitro activity of anti-leishmanial drugs against intracellular Leishmania donovani amastigotes in different types of macrophages.Methods: Mouse peritoneal macrophages (PEMs), mouse bone marrow-derived macrophages (BMMF), human peripheral blood monocyte-derived macrophages (PBMF) and differentiated THP-1 cells were infected with L. donovani. Cultures were incubated with sodium stibogluconate, amphotericin B deoxycholate (Fungizone w ), miltefosine or paromomycin sulphate over six concentrations in 3-fold serial dilutions for 5 days. Analysis was based on percentage inhibition of infected macrophages and EC 50 /EC 90 values estimated using sigmoidal curve-fitting. Results:The rank order of drug activity was the same in the different macrophage populations: amphotericin B. miltefosine .sodium stibogluconate. paromomycin. However, significant (P,0.05) differences were observed between populations. Amphotericin B was more active in PEMs and BMMF (EC 50 0.02-0.06 mM) compared with PBMF and differentiated THP-1 cells (EC 50 0.08 -0.40 mM) and miltefosine was more active in PBMF (EC 50 0.16 -0.74 mM) compared with PEMs and BMMF (EC 50 2.60 -7.67 mM). Sodium stibogluconate displayed highest activity in PBMF (EC 50 1.38-1.89 mg Sb v /mL), followed by Conclusions:In vitro activity of anti-leishmanial drugs is host cell dependent. This has implications for: (i) the evaluation of in vitro drug activity; (ii) the evaluation of drug susceptibility of clinical isolates; and (iii) the standardization of anti-leishmanial drug assays.