Leaves of Peperomia species vary in texture, shape, succulence, lamina size, thickness, coloration, and venation. Each leaf contains only calcium oxalate druses in palisade cells, druses in palisade and raphides in spongy parenchyma, or druses in palisade and prisms in spongy parenchyma. Collectively, these variations create distinct crystal macropatterns. Leaves from 45 species were studied to identify their macropatterns and to compare the macropatterns with molecular data. Microscopic data showed two major crystal macropatterns and five variations of them. All but one species displayed either a single druse in most palisade cells forming one or more uniform crystal layers (81.8%, uniform) or a single druse per cell in palisade cells only above veins forming a reticulate pattern (18.2%, reticulate). Most species (77.3%) did not display any crystals in spongy parenchyma; however, some clades showed spongy parenchyma raphide bundles while others had prisms. Several clades displayed more than one macropattern. Based only on crystal macropatterns, data did not demonstrate a specific phylogenetic trend and failed as synapomorphies for most of the clades. However, crystal macropattern evolution in Peperomia is generally characterized by an increasing complexity of the distribution of druses, raphides, and prisms, with few reversals.