Photodynamic therapy (PDT) appears to be an effective method for the inactivation of Candida species, but limited reports of clinical investigations in this context have been conducted. This randomized clinical trial assessed the efficacy of photodynamic therapy (PDT) using methylene blue (MB) in comparison with fluconazole in the treatment of oral candidiasis in patients undergoing chemotherapy. A total of 20 adult patients undergoing chemotherapy with oral candidiasis were assigned randomly to the photodynamic therapy group (PDT; n=10) receiving six sessions of PDT treatments for 2 weeks, or the control group (CONT; n=10) undergoing treatment with fluconazole (100 mg tablets) once a day for 2 weeks. C. Albicans yeast isolates from the mucosa of the infected area were seeded on Sabouraud agar to measure the colony-forming units (CFUs). This assessment was made immediately before and after the treatment, and after 15, 30, 60 days in the two groups. Patients were assessed for the clinical recovery of oral lesions and improvement of symptoms. PDT decreased the CFUs to a significantly greater extent than fluconazole at the immediate post-treatment assessment (p<0.001) and significantly decreased the oral lesions and clinical symptoms (p=0.017). There was no significant differences between the two groups at 15, 30 and 60 days for the clinical and microbiological evaluations. PDT could better reduce the fungal load and improve the clinical symptoms of oral candidiasis than fluconazole treatment in patients undergoing chemotherapy at the immediate post-treatment assessment. But there is an observed relapse in clinical and microbiological response after 15,30, and 60 days.