Background: Onychomycosis accounts for 30% of all superficial mycoses and 50% of all nail diseases. One of the most studied predisposing factors is diabetes mellitus, with a frequency of onychomycosis of 31.5% in these patients. Many show resistance to standard therapeutics and have “polypharmacy”, which represents a risk for pharmacological interactions. Objective: The objective was to assess the clinical response to therapy, evaluate with histopathology, direct examination with KOH and white-calcofluor, and culture the most frequent etiologic agents associated with the development of onychomycosis in patients with diabetes mellitus. Materials and Methods: A non-randomized, uncontrolled, open-ended, prospective cohort study was conducted on 46 patients with onychomycosis and diabetes mellitus. Treatment was assigned according to clinical findings and specific indications for treatment. Results: From the samples taken for direct examination with KOH and calcofluor-white, culture, and histopathological study, positive results were: 39 (84.1%) patients to the direct examination, 32 (69.6%) to the culture, 27 (65.2%) with a positive histopathological study, and 17 (54.86%) to the calcofluor-white. On clinical evaluation, we found no treatment response in 8 patients (20%), a partial response in 14 patients (25%), and a complete response in 18 patients (45%). Out of the 46 patients evaluated initially, 25 persisted with onychomycosis after six months of follow-up. Conclusion: The prevalence of onychomycosis is increasing and requires correct diagnosis since there are other non-fungal diseases of the nails that resemble onychomycosis. Presumably, the immunosuppression of diabetes, its systemic affection, and the foot abnormalities of a diabetic patient cause more nail dystrophy, an increased fungal load, and treatment resistance.