A complicated history of isolation between Fueguian and Patagonian groups (originated by the appearance of the Straits of Magellan) as much as differences in population structure and life strategies constitute important factors in the clustering pattern of those groups. The aim of this work was to test several hypotheses about population structure and history of Fueguian-Patagonians to propose a model that incorporates predictions for future studies. R matrix methods and matrix permutation analyses were performed upon a data matrix of craniofacial measurements of 441 skulls divided into nine samples pertaining to six Patagonian and three Fueguian populations. Association of biological distances with three matrices representing several settlement patterns was tested using matrix permutation tests. Results of R matrix study show that the minimum genetic distance obtained confirms separation between Fueguians and Patagonians. Moreover, an analysis of residual variances from the expected regression line confirms admixture between Andean and Pampean populations and Araucanian groups, consistent with ethnohistorical observations. A model representing a long history of isolation between Fueguian and Patagonians, rather than a model emphasizing differences in life-strategies, presented the best correlation with the biological distance matrix. Because similar results were already obtained in archaeological, molecular, and morphological studies, a model for the settlement of Tierra del Fuego is proposed. It is summarized by four main hypotheses that can be tested independently by different disciplines in the future. Am. J. Hum. Biol. 14:308–320, 2002. © 2002 Wiley-Liss, Inc.