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INTRODUCTION: Mandibular premolars are some of the most challenging teeth to be treated endodontically, with wide variations in canal anatomy, unexpected morphology, and high incidence of rare configurations. OBJECTIVES: Investigation of root canal anatomical configurations in mandibular premolars in an Egyptian population, and evaluation of Digital Periapical Radiography efficacy in root canal anatomy identification. MATERIALS AND METHODS: The study was approved by the ethical committee at faculty of dentistry, Alexandria University (IRBNO:00010556-IORG0008839). One hundred and eighteen extracted(for periodontal reasons) human mandibular premolars were randomly selected from an Egyptian population at the outpatient clinic of the maxillofacial department in Alexandria University according to selection criteria that ensures the presence of a fully formed root canal system that was neither filled or deteriorated by decay, or restorations, or resorption or cracks. No information regarding age or gender were collected. All samples were mounted in acrylic blocks and scanned by digital periapical radiography from two horizontal angles and then dissected by grinding longitudinally buccolingually till visualizing root canal anatomy highlighted by methylene blue dye. Digital radiographs were analyzed by 5 evaluators who identified the anatomy of each sample according to Vertucci’s classification. Then anatomy displayed by each dissected sample was recorded. Data were statistically analyzed. RESULTS: (Type-I) was the most prevalent configuration (76.3%), followed by Type-V (16.9%) and Type-III (5.1%), and only (1.7%) presented 3-Canal configuration. Periapical radiography failed to correctly detect root canal anatomy in 24 teeth (20.3%). CONCLUSIONS: Presence of more than one canal in mandibular premolars is not rare in the Egyptian population, and periapical radiography is not reliable to identify root canal anatomy of mandibular premolars.