In our ongoing search for new metal-based chemotherapeutic agents against leishmaniasis and Chagas disease, six new ruthenium-ketoconazole (Ru-KTZ) complexes have been synthesized and characterized, including two octahedral coordination complexes cis-fac-[RuIICl2(DMSO)3(KTZ)] (1) and cis-[RuIICl2(bipy)(DMSO)(KTZ)] (2), and four organometallic compounds [RuII(η6-p-cymene)Cl2(KTZ)] (3), [RuII(η6-p-cymene)(en)(KTZ)][BF4]2 (4), [RuII(η6-p-cymene)(bipy)(KTZ)][BF4]2 (5), and [RuII(η6-p-cymene)(acac)(KTZ)][BF4] (6); the crystal structure of (3) is described. The central hypothesis of our work is that combining a bioactive compound like KTZ and a metal in a single molecule results in a synergy that can translate into improved activity and/or selectivity against parasites. In agreement with this hypothesis, complexation of KTZ to RuII in compounds 3-5 produces a marked enhancement of the activity toward promastigotes and intracellular amastigotes of Leishmania major, when compared with uncomplexed KTZ, or with similar Ru compounds not containing KTZ. Importantly, the selective toxicity of compounds 3-5 toward the leishmania parasites, in relation to human fibroblasts and osteoblasts, or murine macrophages, is also superior to those of the individual constituents of the drug. When tested against Trypanosoma cruzi epimastigotes, some of the organometallic complexes displayed an activity and selectivity comparable to that of free KTZ. A dual-target mechanism is suggested to account for the antiparasitic properties of these complexes.