Positron emission tomography (PET) as a method for quality assurance in radiotherapy is well investigated in the case of therapy with carbon ion beams and successfully applied at the Heavy Ion Medical Accelerator at Chiba (HIMAC), Japan, and the Gesellschaft für Schwerionenforschung (GSI), Germany. By measuring the β⁺ activity distribution during the irradiation (in-beam PET), valuable information on the precision of the dose deposition can be obtained. To extend this efficient technique to other radiation treatment modalities may be worthwhile. For example, since positron emitters are generated by high-energy photons with energies above 20 MeV due to (γ, n) reactions (predominantly ¹¹C and ¹⁵O in tissue), in-beam PET seems to be feasible for radiation therapy with high-energy photons as also shown in Geant4 simulations. Quantitative results on the activation of tissue-equivalent materials at hard photon beams were obtained by performing off-beam PET experiments. Homogeneous PMMA phantoms as well as inhomogeneous phantoms were irradiated with high-energy bremsstrahlung. After the irradiation the distributions of the generated positron emitters in the phantoms were measured using a conventional PET scanner. Furthermore, the depth–dose distributions were determined by means of optically stimulated luminescence detectors. In the experiments an activity per dose comparable to that produced in a typical patient irradiation with carbon ions could be achieved for 34 MV bremsstrahlung. In addition, a high contrast in the PET images for materials with different density and stoichiometry could be detected. Thus, further research concerning the development of in-beam PET seems to be worthwhile.