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Background: Sporotrichosis is a subcutaneous or implantation mycosis caused by some species of the genus Sporothrix. Rio de Janeiro state, Brazil, experiences hyperendemic levels of zoonotic sporotrichosis, with increasing cases of disseminated disease, especially in people living with HIV (PLHIV). Involvement of the nasal mucosa is rare and occurs isolated or in disseminated cases, with a delayed resolution. Methodology/Principal findings: This study aimed to describe the epidemiological, clinical, and therapeutic profiles of 37 cases of sporotrichosis with involvement of the nasal mucosa treated at the ear, nose, and throat (ENT) outpatient clinic of the Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, from 1998 to 2020. Data were reviewed from the medical records and stored in a database. The Mann–Whitney test was used to compare the means of quantitative variables, and Pearson chi-square and Fisher's exact tests were used to verify the association between qualitative variables (p<0.05). Most patients were males, students or retirees, with a median age of 38 years, residents in the municipality of Rio de Janeiro, and infected through zoonotic transmission. Disseminated sporotrichosis forms in patients with comorbidities (mostly PLHIV) were more common than the isolated involvement of the mucosa. The main characteristics of lesions in the nasal mucosa were the presence/elimination of crusts, involvement of various structures, mixed appearance, and severe intensity. Due to therapeutic difficulty, itraconazole was combined with amphotericin B and/or terbinafine in most cases. Of the 37 patients, 24 (64.9%) healed, with a median of 61 weeks of treatment, 9 lost follow-up, 2 were still treating and 2 died. Conclusions: Immunosuppression was determinant to the outcome, with worse prognosis and lower probability of cure. Notably in this group, the systematization of the ENT examination for early identification of lesions is recommended to optimize the treatment and outcome of the disease. Author summary: Sporotrichosis is a subcutaneous or implantation mycosis with hyperendemic levels of zoonotic transmission in Rio de Janeiro state, Brazil. The involvement of the nasal mucosa is uncommon and may occur in isolated or disseminated forms of sporotrichosis, but the number of cases has been increasing. We analyzed 37 cases of sporotrichosis with involvement of the nasal mucosa treated at a reference center for infectious diseases. There was a predominance of males, students and retirees, residents in the municipality of Rio de Janeiro, and infected by cats. The median age was 38 years. Disseminated forms of sporotrichosis predominated over isolated involvement of the nasal mucosa. The number of patients with HIV infection also caught our attention. The main characteristics of the nasal mucosa lesions were the presence/elimination of crusts, with an involvement of various structures. Most cases were treated with a combination of antifungal agents and were cured, and two deaths were observed. Immunosuppression directly influenced the prognosis of cure of nasal mucosa sporotrichosis. [ABSTRACT FROM AUTHOR]