Approximately 90% of anatomically modern humans (AMHs) are right-handed. This handedness is related to laterality patterns of the upper limb due to habitual activity patterns which are known to leave marks on the bone structure. Various studies have shown that Neanderthals were also right-handed in very similar proportions to AMHs. Here, for the first time, 3D geometric morphometric techniques are used to study humeral laterality in a Spanish modern human population and to make a comparative study with a Neanderthal sample. Results obtained in the modern human population show a larger right humerus and clear differences in shape laterality. Shape differences in both epiphyses and in the complete humerus could be caused by non-allometric factors. This could suggest different activity pattern in both arms during life. Shaft shape laterality could be explained by allometric factors, i.e. shape variability is related to size variability. Neanderthals show a larger right humerus compared to the left and the mean shape comparison with the common anatomical regions presents a non-significant result. Finally, olecranon fossa width is the only feature that clearly differs between modern humans and Neanderthals, with geometric morphometric and linear measures being wider on the Neanderthal left side and wider on the modern human population right side. This difference may be due to a combination of different factors and behaviors that involve complete extension of the elbow joint.