This study investigates the clinical course, antifungal susceptibility, and genomic sequencing of *Trichophyton indotiniae*, an emerging dermatophyte causing extensive tinea infections that are often unresponsive to terbinafine. The research is a retrospective cohort study of 11 patients with confirmed *T. indotiniae* infections in New York City from May 2022 to May 2023. Patients were recruited from six medical centers, and their clinical features, treatment outcomes, and antifungal susceptibility were analyzed. Key findings include: - **Clinical Features**: Patients had widespread lesions, variable scale, and inflammation, with topical antifungal monotherapy failing in all cases. Diagnostic delays ranged from 3 to 42 months. - **Antifungal Susceptibility**: Terbinafine treatment failed in seven patients at standard doses, with isolates showing amino acid substitutions at positions 393 (L393S) or 397 (F397L) in squalene epoxidase, correlating with elevated terbinafine minimum inhibitory concentrations (MICs) of 0.5 μg/mL or higher. Fluconazole and griseofulvin showed limited efficacy, with no clear correlation between MIC values and clinical outcomes. - **Whole-Genome Sequencing**: US isolates formed a distinct cluster from Indian isolates, suggesting a likely origin in Bangladesh. - **Phylogenetic Analysis**: The study used k-mer analysis to compare US isolates with Indian isolates, revealing a distinct cluster for US isolates. - **Structural Changes**: Homology modeling of *T. indotiniae* squalene epoxidase (SQLE) showed that residues L393 and F397 form part of the hydrophobic binding pocket for terbinafine, while A448T does not, explaining the resistance mechanism. The study highlights the need for prompt clinical recognition and molecular testing to accurately identify *T. indotiniae*, and it reviews current treatment approaches, emphasizing the importance of higher doses and longer durations of antifungal therapy for effective treatment.This study investigates the clinical course, antifungal susceptibility, and genomic sequencing of *Trichophyton indotiniae*, an emerging dermatophyte causing extensive tinea infections that are often unresponsive to terbinafine. The research is a retrospective cohort study of 11 patients with confirmed *T. indotiniae* infections in New York City from May 2022 to May 2023. Patients were recruited from six medical centers, and their clinical features, treatment outcomes, and antifungal susceptibility were analyzed. Key findings include: - **Clinical Features**: Patients had widespread lesions, variable scale, and inflammation, with topical antifungal monotherapy failing in all cases. Diagnostic delays ranged from 3 to 42 months. - **Antifungal Susceptibility**: Terbinafine treatment failed in seven patients at standard doses, with isolates showing amino acid substitutions at positions 393 (L393S) or 397 (F397L) in squalene epoxidase, correlating with elevated terbinafine minimum inhibitory concentrations (MICs) of 0.5 μg/mL or higher. Fluconazole and griseofulvin showed limited efficacy, with no clear correlation between MIC values and clinical outcomes. - **Whole-Genome Sequencing**: US isolates formed a distinct cluster from Indian isolates, suggesting a likely origin in Bangladesh. - **Phylogenetic Analysis**: The study used k-mer analysis to compare US isolates with Indian isolates, revealing a distinct cluster for US isolates. - **Structural Changes**: Homology modeling of *T. indotiniae* squalene epoxidase (SQLE) showed that residues L393 and F397 form part of the hydrophobic binding pocket for terbinafine, while A448T does not, explaining the resistance mechanism. The study highlights the need for prompt clinical recognition and molecular testing to accurately identify *T. indotiniae*, and it reviews current treatment approaches, emphasizing the importance of higher doses and longer durations of antifungal therapy for effective treatment.