Evolutionary relationships among large-bodied species in the gekkonid genus Pachydactylus were investigated using mtDNA sequences from the cytochrome b and 16S ribosomal RNA genes. We combined these data in parsimony and maximum likelihood analyses to address several systematic issues regarding the eight large-bodied taxa, including their phylogenetic position in Pachydactylus as a whole. The large-bodied Pachydactylus do not form a monophyletic group; rather, large size appears to be plesiomorphic. Neither do the large-bodied species exhibiting regional integumentary loss constitute a natural group, as this unusual predator escape mechanism appears in two disparate clades. Both the namaquensis and bibronii groups are monophyletic, the latter being strongly supported. Pachydactylus tuberculosus and Pachydactylus tetensis are consistently basal across analyses, although their phylogenetic position relative to the sister taxon Rhoptropus is uncertain. Equally weighted parsimony recovered a weakly supported Pachydactylus sensu lato (i.e., Pachydactylus tuberculosus and tetensis), whereas weighted parsimony and maximum likelihood analyses depict tetensis and tuberculosus as taxa sister to Pachydactylus Rhoptropus. Concordance across all analytical methods lends validity to the synonyms Homodactylus Gray and Elasmodactylus Boulenger, which could be resurrected without compromising the monophyly of the remaining Pachydactylus.