Background: Oropharyngeal dysphagia harms all aspects of a person’s life, including behaviors, activities, and social situations. Quality of life is a multidimensional concept. The dysphagia handicap index (DHI) is a patient-reported outcomes tool that evaluates the different dimensions of quality of life in three physical, emotional, and functional factors in English-speaking countries. The validity of the Persian version of the dysphagia handicap index (DHI) has been evaluated in a study, but the reliability and factor analysis of the Persian version has not been investigated in any study. Objectives: This study aimed to investigate the factor structure analysis and reliability of the Persian version of the dysphagia handicap index (P-DHI). Methods: In this cross-sectional study, 100 patients with oropharyngeal dysphagia (mean age 55.69 ± 15.04, 53 women) completed the dysphagia handicap index (DHI). The severity of dysphagia was defined as follows: 1 for no dysphagia (normal), 2 and 3 for mild, 4, and 5 for moderate and 6 and 7for severe. Construct validity was examined by confirmatory factor analysis (CFA). Cronbach’s alpha and intraclass correlation coefficient (ICC) were performed to evaluate the internal consistency and test-retest reliability of the P-DHI, respectively. Results: The results of CFA provided support for a second-order three-factor model of P-DHI (χ2 = 484.61, df = 273, (P = 0.0001), χ2/df = 1.77; CFI = 0.901; RMSEA = 0.088 and SRMR = 0.010). The Cronbach’s alpha for physical, functional, and emotional subscales and total score were 0.751, 0.836, 0.773, and 0.900, respectively. The test-retest reliability of the P-DHI for the total score and subscales was high (ICC: 0.952 - 0.988). Furthermore, a significant relationship was found between the P-DHI total score and self-reported severity of dysphagia (P = 0.0001), while there were no relationships between P-DHI total score and age (P = 0.223), sex (P = 0.936), level of education (P = 0.113), disease duration (P = 0.126). Conclusions: The P-DHI is a reliable and valid instrument for assessing the disabling effects of swallowing disorders on the one’s Quality of Life in Iranian patients with oropharyngeal dysphagia due to a variety of diseases. Also, the CFA findings provide support for the tree-factor structure of the P-DHI and the use of the subscales as distinct variables.