INTRODUCTION: Mucormycosis, hyalohyphomycosis, chromoblastomycosis, and fungal mycetoma are rare invasive fungal infections (IFIs) that cause significant morbidity and mortality in immunocompromised patients. Few effective treatment options are available for these IFIs. METHODS: We performed a systematic literature review of MEDLINE and Embase to identify studies published from 2005 (year of posaconazole approval) to October 22, 2022, reporting the efficacy/effectiveness of posaconazole monotherapy or combination therapy for treating mucormycosis, hyalohyphomycosis, chromoblastomycosis, and mycetoma. Positive outcomes or positive clinical outcomes were defined as reporting of a positive efficacy/effectiveness measure (i.e., no relapse, response, cure, radiological improvement, clinical / symptom improvement, or survived therapy). RESULTS: Of 3207 articles identified (after removing duplicates), 533 articles (mostly case reports) were included. Positive clinical outcomes with posaconazole therapy were observed in most patients with mucormycosis (74.8%, 1197/1601), hyalohyphomycosis (58.5%, 62/106), chromoblastomycosis (90.5%, 19/21), and mycetoma (100%, 5/5). Overall survival was around 70% or greater across the IFIs examined. Positive response was higher in second-line monotherapy than first-line monotherapy in mucormycosis and chromoblastomycosis. Higher mortality was observed with combination therapy than monotherapy in mucormycosis and hyalohyphomycosis infections (except for first-line use in mucormycosis). Positive clinical outcome was 78.6% and overall survival was 78.6% in 323 coronavirus disease (COVID)-associated mucormycosis infection cases. CONCLUSION: Despite the rarity of these IFIs, substantial data have been published since posaconazole was initially approved in 2005, and the real-world case reports demonstrate that posaconazole is an effective therapeutic option alone or in combination for the treatment of these rare IFIs.