Background: The aim of this study was to assess the feasibility and diagnostic accuracy of an optimized 111Indium-diethylenetriamine-penta-acetic-acid single-photon-emission computed tomography (CT) (111In-DTPA SPECT-CT) examination in patients with suspected intrathecal drug delivery (ITDD) failure. Materials and Methods: Retrospective analysis of routinely collected observational data from a case series of patients in the setting of the academic Center for Pain Medicine, Departments of Radiology and Nuclear Medicine and Neurosurgery. Twenty-seven patients participated between January 2014 and January 2019. Thirty-six optimized examinations including standardized pump flow rate with additional SPECT-CT imaging and a stepwise standardized analysis were performed. A 10 mL mixture of medication and 20 MBq 111In-DTPA was injected into the pump reservoir. Planar and SPECT-CT images were acquired at 24, 48, and 72 hours (h) after injection and at 96 hours and/or seven days, if needed. All images were reassessed by the first two authors using an optimized procedure. Results and Conclusions: Twenty-two abnormalities were identified in 21 examinations, with these abnormalities consisting of leakage (n = 7), spinal catheter obstruction (n = 7), and cerebrospinal fluid flow obstruction (n = 8). Interventions (n = 19) confirmed the cause of ITDD failure. A false-positive finding at follow-up (n = 1) and a false-negative finding (n = 1) were encountered. Sensitivity was 95% (20/21) and the specificity 93% (14/15). A significant difference (p < 0.001) was found between the accuracy of the conventical and the optimized analysis. The optimized111In-DTPA SPECT-CT examination is a powerful diagnostic tool for detecting the cause of ITDD failure.