Background: Incisor-molar hypomineralization (IMH) presents various clinical characteristics that generate confusion for differential diagnosis with other enamel abnormalities such as amelogenesis imperfecta (AI). Purpose: To analyze dental, facial, and skeletal characteristics in people with IMH and compare them to those with AI in order to identify diagnostic differences between these two enamel defects. Methods: Analytical observational study. Twelve 7-to-10-year-olds with IMH and 10 8-to-49-year-olds with AI were studied. IMH was assessed according to the European Academy of Pediatric Dentistry’s diagnostic criteria, Mathu Maju’s criteria (2006), and Neeti Mittal’s phenotypic classification (2016), while Witkop’s criteria (1989) were used to analyze AI. Clinical, radiographic, facial, and skeletal analyses were performed to establish IMH phenotypes, information that was fed into an Excel® database for subsequent statistical analysis (SPSS 22.0) (p<0.05). Results: Statistically significant differences were found between IMH and AI. Only patients with IA presented dilaceration, dental agenesis, and taurodontism. There are similarities regarding facial features such as facial asymmetry, increased intercanthal distance, decreased lower third, biprochelia and convex profile, and occlusal features such as molar relationship, canine relationship, and overjet. Concerning transverse relationships, micrognathism was more frequent in IMH and in vertical relationships, deep overbite was greater in IMH than in AI. Conclusions: The main differences between IMH and AI were evident in skeletal characteristics and associated dental alterations.