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Itraconazole(ITZ) – an antifungal agent of the azole class – is clinically used to treat a variety of fungal infections. Among them, paracoccidioidomycosis (PCM), a fungal infection caused by Paracoccidioides brasiliensis,is the most prevalent systemic fungal infection in Brazil as well as in many countries in South America. Conventional treatments of PCM with itraconazole include oral solution and capsule formulations, both associated to many side effects such as nausea, vomiting, abdominal pain, diarrhea, headaches and mild alopecia. Drug delivery systems enables the development of new pharmaceutical formulations for the controlled delivery of drugs, which can avoid many of the problems related to low efficacy and side effects of traditional drugs. In this study, using HPLC, we determined the biodistribution of ITZ administered both, as a nanoparticle presentation (PLGA nanoparticle coated with DMSA – ITZ-NANO), as well as oral solution (Free ITZ) in healthy mice. We also compared the therapeutic efficiency as well as toxicity of both forms of ITZ presentations in the treatment of PCM infected mice using clinical, biochemical and histological approaches. Biodistribution demonstrated higher accumulation of ITZ in lung, liver and spleen of ITZ from ITZ-NANO. ITZ-NANO treatment of chronic PCM was capable of eliminate fungal cells from lungs and avoided the side effects of alopecia and increment of liver enzymes concentration. The proposed treatment, with a lower administration dose of ITZ-NANO and decreased number of administrations, demonstrated promising potential with higher success rate, and less stress for the patient with usage of this nanomaterial.