Madtsoiidae is a speciose family of extinct snakes that achieved a wide Gondwanan and trans-Tethyan distribution by the Late Cretaceous, surviving until the late Pleistocene. Gigantophis garstini, the first and largest described madtsoiid, was recovered from the upper Eocene of Fayum, Egypt. The 20 vertebrae that constitute the syntype have only received brief description, hindering the referral of specimens to this taxon and our understanding of madtsoiid interrelationships in general. A detailed redescription of the syntype material demonstrates the validity of Gigantophis, based on two autapomorphies (including a strongly depressed neural canal in posterior trunk vertebrae) and a unique combination of characters. Referred material from the lower Paleocene of Pakistan differs significantly, and we restrict Gigantophis to the middle—late Eocene of North Africa. Using a model of morphological variation in extant snakes, we estimate that Gigantophis was 6.9 ±0.3 m long. A phylogenetic analysis using the largest sample of putative madtsoiids (20 operational taxonomic units) and a revised and augmented matrix (148 characters) places Gigantophis as sister taxon to the latest Cretaceous Indian snake Madtsoia pisdurensis. Whereas our topology might suggest that a dispersal route was present between India and North Africa in the latest Cretaceous—early Paleogene, an evaluation of putative dispersal routes leads us to conclude that the paleobiogeography of Madtsoiidae is best explained by a poorly sampled, earlier widespread distribution in Africa, Indo-Madagascar, and South America. In contrast, latest Cretaceous madtsoiid occurrences in Europe might be explicable by trans-Tethyan dispersal from Africa across the Apulian Route.