Background: In India, an increased prevalence of chronic, recurrent, and recalcitrant dermatophytosis is being observed. The present study assesses the clinico-mycological profile, antifungal drug sensitivity and therapeutic efficacy of various systemic antifungal drug regimens, in extensive dermatophytosis patients of coastal Andhra Pradesh. Materials and Methods: One hundred and fifty clinically diagnosed cases of extensive dermatophytosis affecting more than one body region were enrolled. Skin samples were taken for direct microscopy and fungal culture. Antifungal drug sensitivity testing was done with broth microdilution test. Therapeutic efficacy of systemic antifungal drug regimens was determined by randomly dividing the patients into 5 groups of 30 each. Results: The most common clinical patterns observed were tinea corporis et cruris (62.7%) followed by extensive tinea corporis (11.3%). KOH and culture positivity were seen in 132 (88%) and 84 cases (56%) respectively. Trichophyton mentagrophytes was isolated in 78 cases (92.8%) followed by Microsporum gypseum in 6 patients (7.1%). The overall mean minimum inhibitory concentration values for itraconazole (0.04 μg/mL) were low when compared to griseofulvin (4.61 μg/mL) and terbinafine (6.9 μg/mL) ( P < 0.05). Combination of itraconazole and griseofulvin achieved highest clinical and mycological cure rates (93.1%). Among patients receiving single drugs, itraconazole had higher cure rates (71.4%) compared to terbinafine (59.2%) and griseofulvin (53.8%) ( P < 0.05). Conclusion: Trichophyton mentagrophytes has replaced Trichophyton rubrum as the predominant species causing dermatophytosis in Andhra Pradesh, presenting with a severe phenotype. Itraconazole was found to be the most effective drug both in vivo and in vitro . A combination of systemic drugs should be considered in cases of monotherapy failure and in recalcitrant dermatophytosis.