Atomic force microscopy (AFM) experiments and molecular dynamics (MD) simulations were conducted to examine single-asperity friction as a function of load, surface orientation, and sliding direction on individual crystalline grains of diamond in the wearless regime. Experimental and simulation conditions were designed to correspond as closely as state-of-the-art techniques allow. Both hydrogen-terminated diamond (111)(1 x 1)-H and the dimer row-reconstructed diamond (001)(2 x 1)-H surfaces were examined. The MD simulations used H-terminated diamond tips with both flat- and curved-end geometries, and the AFM experiments used two spherical, hydrogenated amorphous carbon tips. The AFM measurements showed higher adhesion and friction forces for (001) vs (111) surfaces. However, the increased friction forces can be entirely attributed to increased contact area induced by higher adhesion. Thus, no difference in the intrinsic resistance to friction (i.e., in the interfacial shear strength) is observed. Similarly, the MD results show no significant difference in friction between the two diamond surfaces, except for the specific case of sliding at high pressures along the dimer row direction on the (001) surface. The origin of this effect is discussed. The experimentally observed dependence of friction on load fits closely with the continuum Maugis-Dugdale model for contact area, consistent with the occurrence of single-asperity interfacial friction (friction proportional to contact area with a constant shear strength). In contrast, the simulations showed a nearly linear dependence of the friction on load. This difference may arise from the limits of applicability of continuum mechanics at small scales, because the contact areas in the MD simulations are significantly smaller than the AFM experiments. Regardless of scale, both the AFM and MD results show that nanoscale tribological behavior deviates dramatically from the established macroscopic behavior of diamond, which is highly dependent on orientation.