Background: Posaconazole (PSCZ) is a broad-spectrum azole antifungal drug that shows potent antifungal activity to filamentous fungi and yeast-like fungi including Mucorales. Objective and Method: A randomized, active-controlled, open-label, comparative study to assess the safety and efficacy of PSCZ in Japanese subjects with deep-seated fungal infection was conducted (MK-5592 Protocol 101, ClinicalTrials.gov Identifier: NCT02180165). Subjects with aspergillosis were randomized at 2:1 ratio to PSCZ (57 subjects) or voriconazole (VRCZ, 27) and subjects with mucormycosis were allocated to PSCZ (3), and received study therapy at a maximum of 84 days. The overall response was assessed at Day 42, Day 84, or the end of treatment, and adverse events were followed up to 14 days after the end of treatment. Results: The overall response rates were 40.0% (2/5) for PSCZ and 100.0% (3/3) for VRCZ in invasive aspergillosis (at Day 42), 58.3% (28/48) for PSCZ and 87.0% (20/23) for VRCZ in chronic pulmonary aspergillosis (at Day 84), and 100.0% (3/3) for PSCZ in mucormycosis (at end of treatment) respectively. The common drug-related adverse events were pyrexia (22.8%), hypokalemia (15.8%), hepatic function abnormality (14.0%), and hypertension (14.0%) in PSCZ; and photophobia (29.6%), visual impairment (14.8%), and hepatic function abnormality (14.8%) in VRCZ. Conclusion: PSCZ was shown to be safe and effective in Japanese patients with aspergillosis and mucormycosis, pointing to its usefulness against fungal infections with limited treatment choices in Japan.