Visual comparisons are pervasive in science, technology, engineering, and mathematics (STEM) instruction and practice. In previous work, adults' visual comparisons of simple stimuli were faster and more accurate when the layout of a display facilitated alignment of corresponding elements--the "spatial alignment principle" (Matlen et al., 2020). Here, we asked whether the spatial alignment principle extends to rich, educationally relevant stimuli, and how prior experience and spatial skill relate to spatial alignment effects. Participants were asked to find an incorrect bone within a skeleton, presented individually or paired with a correct skeleton in a layout that did (direct placement) or did not (impeded placement) support alignment (Kurtz & Gentner, 2013). Consistent with the spatial alignment principle, undergraduates (Study 1) showed an advantage of direct over impeded placement. Middle schoolers (Study 2) showed a direct advantage on items presented in atypical orientations. That atypical items showed the strongest effects suggests that direct placement may help most when materials are less familiar. However, neither individual differences in undergraduates' STEM course history, nor undergraduates' or middle schoolers' spatial skills moderated spatial alignment effects. Thus, applying the spatial alignment principle in science, technology, engineering, and mathematics has potential to improve visual comparisons, especially those that are challenging, for students of all spatial skill levels. [This is the online first version of an article published in "Journal of Experimental Psychology: Applied" (ISSN 1076-898X).]