Abstract INTRODUCTION Localization-related epilepsy frequently involves mesial temporal lobe structures (MTLS), but sometimes presurgical workup can be confusing since shortage of definite structural lesional evidence or inconsistency among multimodal tools. Occasionally invasive workup is applied. This study evaluates the application of multimodal workup in surgical strategy making of localization-related epilepsy involving MTLS. METHODS Our study includes patients with significant or subtle MTLS abnormality (or magnetic resonance imaging (MRI) negative) in 3.0T MRI and then underwent resective surgeries encompassing MTLS. In addition to conventional workup tools, accurate EEG source imaging (ESI) technique based on individual head models is available. Patients accepted either 1-stage resective surgeries or staged surgeries (SEEG implantation + stage-2 resective surgeries). Contributions of structural MRI, fluorodeoxyglucose-positron emission tomography (FDG-PET), accurate ESI, and ictal EEG to surgical strategies were evaluated by criteria defining epileptogenic zone (resective scope in cases with good outcome). RESULTS Thirty-five patients who achieved Engel grade I + II outcome after resective surgeries were included. All together, 68.6% cases showed ESI sources totally falling into resective scope. 42.9% ictal EEG estimates, 57.1% PET focal hypometabolistic regions, 74.3% MRI structural lesions fitted the resective scope/side. In total, 75% 1-stage cases showed ESI sources being confined in MTLS region, while PET showed focal hypometabolism in 66.7% and MRI indicated single MTLS lesions (including subtle ones) in 79.2% cases. In total, 54.5% ESI sources and 63.6% MRI abnormality (single, including subtle ones) in staged cases showed complete concordance with SEEG findings. In subtle lesional/MRI negative cases, ESI generated sources confined within MTLS in 77.8% cases, while PET estimates are focally localizing in 44.4% cases and 55.6% showed subtle MRI lesions which were firstly diagnosed “negative.” CONCLUSION Multimodal noninvasive workup are contributable to help decide strategy of 1-stage resective surgeries and SEEG plans in localization-related epilepsy. High-quality structural MRI, accurate ESI technique based on scalp EEG as well as FDG-PET are key to presurgical planning of epilepsy involving MTLS.