Numerous studies have described altered patterns of craniofacial form in the unaffected relatives of individuals with nonsyndromic clefts. Unfortunately, results from such studies have been highly variable and have failed to provide a reliable method for differentiating “at-risk” relatives from controls. In the present study, we compared craniofacial shape between a sample of unaffected relatives (33 females; 14 males) from cleft multiplex families and an equal number of age/sex/ethnicity-matched controls. Sixteen x,y,z facial landmark coordinates derived from 3D photogrammetry were analyzed via Euclidean Distance Matrix Analysis, while 14 additional linear distances were analyzed via t tests. A subset of variables was then entered into a discriminant function analysis (DFA). Compared to controls, female unaffected relatives demonstrated increased upper facial width, midface reduction and lateral displacement of the alar cartilage. DFA correctly classified 70% of female unaffected relatives and 73% of female controls. Male unaffected relatives demonstrated increased upper facial and cranial base width, increased lower facial height and decreased upper facial height compared with controls. DFA correctly classified 86% of male unaffected relatives and 93% of male controls. In both sexes, upper facial width contributed most to group discrimination. Following DFA, unaffected relatives were assigned to risk/liability classes based on the degree of phenotypic divergence from controls. Results indicate that craniofacial shape differences characterizing unaffected relatives are partly sex-specific and are in broad agreement with previous reports. These findings further suggest that a quantitative assessment of the craniofacial phenotype may allow for the identification of susceptible individuals within nonsyndromic cleft families. © 2008 Wiley-Liss, Inc.