Purpose: Micromilieu-dependent quantification of γH2AX after irradiation in vivo and correlation with local tumour control. Materials and methods: Local tumour control was evaluated after irradiation of FaDu and SKX xenografts with ambient single doses. γH2AX foci were quantified in perfused and unperfused regions after different irradiation doses and at different time points. Results: The TCD ₅₀ of FaDu was 2-times higher compared to SKX (28.0 Gy [95% C.I. 24.6; 31.3 Gy] for FaDu; 14.9 Gy [10.9; 18.9] for SKX, p < 0.001). The induction of foci did not differ between the tumour models. Residual foci were twice higher in perfused SKX regions compared to FaDu, no difference was observed in the non-perfused region between both tumour models. The number of residual foci increased with a 2-times higher slope in perfused SKX-regions compared to FaDu, while no difference was detected in unperfused regions. Already within the perfused regions, this slope decreased with distance from perfused vessels. Conclusion: The dose-response of residual γH2AX foci is highly dependent on tumour cell oxygenation in well perfused areas. This dependence decreases further away from tumour vessels. Only γH2AX evaluation in perfused tumour areas can distinguish between the different radiocurability of the two tumour models.