Background: Central necrosis can be detected on [18F]FDG PET/CT as a region with little to no tracer uptake. Currently, there is no consensus regarding the inclusion of regions of central necrosis during volume of interest (VOI) delineation for radiomic analysis. The aim of this study was to assess how central necrosis affects radiomic analysis in PET. Methods: Forty-three patients, either with non-small cell lung carcinomas (NSCLC, n = 12) or with pheochromocytomas or paragangliomas (PPGL, n = 31), were included retrospectively. VOIs were delineated with and without central necrosis. From all VOIs, 105 radiomic features were extracted. Differences in radiomic features between delineation methods were assessed using a paired t-test with Benjamini–Hochberg multiple testing correction. In the PPGL cohort, performances of the radiomic models to predict the noradrenergic biochemical profile were assessed by comparing the areas under the receiver operating characteristic curve (AUC) for both delineation methods. Results: At least 65% of the features showed significant differences between VOIvital-tumour and VOIgross-tumour (65%, 79% and 82% for the NSCLC, PPGL and combined cohort, respectively). The AUCs of the radiomic models were not significantly different between delineation methods. Conclusion: In both tumour types, almost two-third of the features were affected, demonstrating that the impact of whether or not to include central necrosis in the VOI on the radiomic feature values is significant. Nevertheless, predictive performances of both delineation methods were comparable. We recommend that radiomic studies should report whether or not central necrosis was included during delineation.