This study determines the optimal clinical scenarios for gold nanoparticle dose enhancement as a function of irradiation conditions and potential biological targets using megavoltage x-ray beams. Four hundred and eighty clinical beams were studied for different potential cellular or sub-cellular targets. Beam quality was determined based on a 6 MV linac with and without a flattening filter for various delivery conditions. Dose enhancement ratios DER = D(GNP)/D(water) were calculated for all cases using the GEANT4 Monte Carlo code and the CEPXS/ONEDANT radiation transport deterministic code. Dose enhancement using GEANT4 agreed with CEPXS/ONEDANT. DER for unflattened beams is ∼2 times larger than for flattened beams. The maximum DER values were calculated for split-IMRT fields (∼6) and for out-of-field areas of an unflattened linac (∼17). In-field DER values, at the surface of gold nanoparticles, ranged from 2.2 to 4.2 (flattened beam) and from 3 to 4.7 (unflattened beams). For a GNP cluster with thicknesses of 10 and 100 nm, the DER ranges from 14% to 287%. DER is the greatest for split-IMRT, larger depths, out-of-field areas and/or unflattened linac. Mapping of a GNP location in tumor and normal tissue is essential for efficient and safe delivery of nanoparticle-enhanced radiotherapy.