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Spatially fractionated radiotherapy is a strategy to overcome the main limitation of radiotherapy, i.e., the restrained normal tissue tolerances. A well-known example is Grid Therapy, which is currently performed at some hospitals using megavoltage photon beams delivered by Linacs. Grid Therapy has been successfully used in the management of bulky abdominal tumors with low toxicity. The aim of this work was to evaluate whether an improvement in therapeutic index in Grid Therapy can be obtained by implementing it in a flattening filter-free (FFF) Linac. The rationale behind is that the removal of the flattening filter shifts the beam energy spectrum towards lower energies and increase the photon fluence. Lower energies result in a reduction of lateral scattering and thus, to higher peak-to-valley dose ratios (PVDR) in normal tissues. In addition, the gain in fluence might allow using smaller beams leading a more efficient exploitation of dose–volume effects, and consequently, a better normal tissue sparing.Monte Carlo simulations were used to evaluate realistic dose distributions considering a 6 MV FFF photon beam from a standard medical Linac and a cerrobend mechanical collimator in different configurations: grid sizes of 0.3 × 0.3 cm2, 0.5 × 0.5 cm2, and 1 × 1 cm2 and a corresponding center-to-center (ctc) distance of 0.6, 1, and 2 cm, respectively (total field size of 10 × 10 cm2). As figure of merit, peak doses in depth, PVDR, output factors (OF), and penumbra values were assessed.Dose at the entrance is slightly higher than in conventional Grid Therapy. However, it is compensated by the large PVDR obtained at the entrance, reaching a maximum of 35 for a grid size of 1 × 1 cm2. Indeed, this grid size leads to very high PVDR values at all depths (≥ 10), which are much higher than in standard Grid Therapy. This may be beneficial for normal tissues but detrimental for tumor control, where a lower PVDR might be requested. In that case, higher valley doses in the tumor could be achieved by using an interlaced approach and/or adapting the ctc distance. The smallest grid size (0.3 × 0.3 cm2) leads to low PVDR at all depths, comparable to standard Grid Therapy. However, the use of very thin beams might increase the normal tissue tolerances with respect to the grid size commonly used (1 × 1 cm2). The gain in fluence provided by FFF implies that the important OF reduction (0.6) will not increase treatment time. Finally, the intermediate configuration (0.5 × 0.5 cm2) provides high PVDR in the first 5 cm, and comparable PVDR to previous Grid Therapy works at depth. Therefore, this configuration might allow increasing the normal tissue tolerances with respect to Grid Therapy thanks to the higher PVDR and thinner beams, while a similar tumor control could be expected.The implementation of Grid Therapy in an FFF photon beam from medical Linac might lead to an improvement of the therapeutic index. Among the cases evaluated, a grid size of 0.5 × 0.5 cm2 (1-cm-ctc) is the most advantageous configuration from the physics point of view. Radiobiological experiments are needed to fully explore this new avenue and to confirm our results.