Background: Drug-resistant epilepsy (DRE) is a commonly faced problem in epilepsy practice associated with great psychosocial consequences. This work aimed to study the role of seizure semiology analysis (SSA), long-term EEG monitoring, high field strength MRI, and positron emission tomography (PET) scan of the brain to confirm the diagnosis of true-RDE cases as well as seizure onset zone (SOZ) localization. Methods: This study was conducted on 67 DRE patients subjected to SSA, long-term video EEG, 3-Tesla MRI brain, and 18-FDG PET scan of brain. Results: Forty-three patients had true-DRE and 24 had non-epileptic episodic events (NEEE). The former group consisted of 23 patients with temporal lobe, 17 with frontal lobe, and 3 with occipital lobe epilepsies. Forty-eight patients had abnormal EEG included all patients with true-DRE and 5 patients with NEEE. Thirty patients had abnormal MRI brain findings in the form of mesial temporal sclerosis and/or focal cortical dysplasia. Sixteen true-DRE patients with normal 3-T MRI underwent PET scan of the brain where regional hypometabolism was detected in 14 (87.5%) of them. Conclusion: Practicing with DRE patients' needs meticulous assessment through detailed SSA, adequate neurophysiological long-term video EEG monitoring, and thorough neuroradiological investigation (structural and/or functional) to confirm the diagnosis of true-DRE and localize the SOZ as well as identification of patients with NEEE.