Photodynamic therapy (PDT) is a medical modality that uses a combination of visible light and a photosensitive compound in the presence of oxygen. It is widely used to treat non-melanoma skin cancer; other indications are being investigated, especially onychomycosis. Eighty patients with toenail onychomycosis were enrolled and completed this randomized, parallel, placebo-controlled study. For 24 weeks, 40 patients (Group A) were treated with one placebo capsule per week and sessions of 2% methylene blue aqueous solution irradiated with light emission diode device (MBLED/PDT) with 18 J/cm2; and another 40 patients (Group B) were treated with 300 mg oral fluconazole per week and sessions of placebo PDT (haematoxylin-diluted 1 : 10). The use of MBLED/PDT consisted of sessions with an interval of 15 days between each session for 6 months. Microbiological and clinical cure was assessed at 1 and 12 months posttreatment. Group A (MBLED/PDT) patients showed a significant response (p < 0.002) compared with Group B (fluconazole), especially in patients who required nail abrasion (p < 0.001). The MBLED/PDT is safe, effective, and well tolerated; it promotes a favorable outcome with good patient adherence and may be considered as a practical and feasible treatment option for toenail onychomycosis.