Oncologic 18F-FDG PET/CT acquisition and reconstruction protocols need to be optimized for both quantitative and detection tasks. To date, most studies have focused on either quantification or noise, leading to quantitative harmonization guidelines or appropriate noise levels. We developed and evaluated protocols that provide harmonized quantitation with optimal amounts of noise as a function of acquisition parameters and body mass. Methods: Multiple image acquisitions (n = 17) of the International Electrotechnical Commission/National Electrical Manufacturers Association PET image-quality phantom were performed with variable counting statistics. Phantom images were reconstructed with 3-dimensional ordered-subset expectation maximization (OSEM3D) and point-spread function (PSF) for harmonized quantification of the contrast recovery coefficient of the maximum pixel value (CRCmax ). The lowest counting statistics that resulted in compliance with European Association of Nuclear Medicine recommendations for CRCmax and CRCmax variability were used as optimization metrics. Image noise in the liver of 48 typical oncologic 18F-FDG PET/CT studies was analyzed with OSEM3D and PSF harmonized reconstructions. We also evaluated 164 additional 18F-FDG PET/CT reconstructed list-mode images to derive analytic expressions that predict image quality and noise variability. Phantom-to-subject translational analysis was used to derive optimized acquisition and reconstruction protocols. Results: For harmonized quantitation levels, PSF reconstructions yielded decreased noise and lower CRCmax variability than regular OSEM3D reconstructions, suggesting they could enable a decreased activity regimen for matched performance. Conclusion: PSF reconstruction with a 7-mm postprocessing filter can provide harmonized quantification performance and acceptable image noise levels with injected activity, duration, and mass settings using a 260 MBq⋅s/kg acquisition parameter at scan time. Similarly, OSEM3D with a 5-mm postprocessing filter can provide similar performance with 401 MBq⋅s/kg.