To test whether there are differences between living lineages of domestic guinea pigs Cavia porcellus, we studied 118 specimens from six breeds collected along six Andean countries as well as 15 from the wild cavy species (Cavia tschudii). The mean weight and body length of 15 adult wild cavies (295±31 g, 242±8.3 mm) were significantly smaller than 25 creole guinea pigs from Bolivia and Chile (639±157 g, 287±23.7 mm, respectively). Eighteen laboratory/pet guinea pigs (including the English Pirbright breed) were also smaller (900±173 g, 308±21 mm) than 25 improved ones from Peru (Tamborada breed, 1241±75.4 g, 317±12 mm) and Ecuador (Auqui breed, 1138±65.5 g, 307±8 mm). Similar size increases appeared in the first axis of a principal component analysis of six skeletal measurements, recovering 84% of total variation. Phylogenetic and haplotype analyses of complete cytochrome b gene sequences consistently joined all 22 domestic individuals (13 shared unambiguous substitutions, 100% bootstrap in 1000 replicates), probably from a single first ancient domestication in the western Andes. Six laboratory/pet sequences were also joined within a common branch (six shared substitutions, 96% bootstrap), probably from a documented European second phase. By contrast, those from improved Auqui joined a northern creole subgroup (one shared substitution, 84% bootstrap), and those from Nativa and improved Tamborada clustered together and with a southern creole subgroup (four shared substitutions, 86% bootstrap); this suggests at least two independent modern events during a more complex third phase, producing two improved guinea pigs selected for size and meat. Cavia tschudii sequences showed some unexpected geographic variation.