Abstract Objective . Reliable radionuclide production yield data are a prerequisite for positron-emission-tomography (PET) based in vivo proton treatment verification. In this context, activation data acquired at two different treatment facilities with different imaging systems were analyzed to provide experimentally determined radionuclide yields in thick targets and were compared with each other to investigate the impact of the respective imaging technique. Approach. Homogeneous thick targets (PMMA, gelatine, and graphite) were irradiated with mono-energetic proton pencil-beams at two distinct energies. Material activation was measured (i) in-beam during and after beam delivery with a double-head prototype PET camera and (ii) offline shortly after beam delivery with a commercial full-ring PET/CT scanner. Integral as well as depth-resolved β + -emitter yields were determined for the dominant positron-emitting radionuclides 11 C, 15 O, 13 N and ( in-beam only) 10 C. In-beam data were used to investigate the qualitative impact of different monitoring time schemes on activity depth profiles and their quantitative impact on count rates and total activity. Main results. Production yields measured with the in-beam camera were comparable to or higher compared to respective offline results. Depth profiles of radionuclide-specific yields obtained from the double-head camera showed qualitative differences to data acquired with the full-ring camera with a more convex profile shape. Considerable impact of the imaging timing scheme on the activity profile was observed for gelatine only with a range variation of up to 3.5 mm. Evaluation of the coincidence rate and the total number of observed events in the considered workflows confirmed a strongly decreasing rate in targets with a large oxygen fraction. Significance . The observed quantitative and qualitative differences between the datasets underline the importance of a thorough system commissioning. Due to the lack of reliable cross-section data, in-house phantom measurements are still considered a gold standard for careful characterization of the system response and to ensure a reliable beam range verification.