OBJECTIVE: Coordinated European projects relying on standardized methods are needed to identify health inequalities across Europe. This study aimed to compare fitness, fatness, and cardiometabolic risk between urban adolescents from the south and center-north of Europe and to explore whether physical activity (PA) and other factors might explain these differences. METHODS: The Healthy Lifestyle in Europe by Nutrition in Adolescence cross-sectional project comprised 3528 adolescents from the south (4 cities) and central-north (6 cities) of Europe, 1089 of whom provided blood samples for analysis. Fitness (strength, speed-agility, and cardiorespiratory fitness), total and abdominal fatness (anthropometry and bioelectrical impedance), and cardiometabolic risk (z scores including fitness, fatness, blood lipids, insulin resistance, and blood pressure) were assessed. The analyses were adjusted for socioeconomic factors, objectively measured PA (accelerometry), total energy intake and diet quality, and genetic variants of the FTO rs9939609 polymorphism. RESULTS: Adolescents from southern Europe were less fit and fatter according to all markers (P < .001). Differences in cardiometabolic risk scores were not consistent. Adolescents from the south were less active and this would largely explain the differences observed in speed-agility and cardiorespiratory fitness. Differences in total and abdominal fatness could not be explained by PA, energy intake, diet quality, or FTO rs9939609 polymorphism. CONCLUSIONS: Fitness and fatness levels indicate that urban adolescents from the south are less healthy than those from central-northern Europe. Our data suggest that differences in PA might explain differences in important health-related fitness components, yet factors explaining the differences in fatness encountered remain unknown.