OBJECTIVE: To investigate the relationship between handgrip strength (HGS) and sex, anthropometrics, body composition, and cardiovascular fitness has not been well studied in children, adolescents, and young adults. STUDY DESIGN: A single-center retrospective review of patients <25 years old without known heart disease and referred for clinical cardiopulmonary exercise testing was performed. Each patient underwent HGS testing, bioelectrical impedance body composition analysis, and cardiopulmonary exercise testing. Relationships between variables were assessed using the Pearson correlation coefficient, linear regression, cubic spline, and multivariable analysis. Comparisons by sex were performed using the Student test. RESULTS: The study included 316 patients without heart disease (age 15.1 ± 2.4 years old; 35% male). Male patients had greater peak dominant (34.4 ± 11.9 kg vs 27.8 ± 6.2 kg;  < .001) and nondominant (32.1 ± 11.1 kg vs 25.3 ± 6.0 kg;  < .001) HGS than female patients, with these differences more noticeable in the teenage years. Peak dominant HGS averaged 30.2 ± 9.3 kg and was correlated with age ( = 0.49,  < .001) and weight ( = 0.56,  < .0001); peak dominant HGS was even more strongly correlated with total body skeletal muscle mass (r = 0.80,  < .001), peak oxygen consumption (mL/min) (r = 0.69,  < .0001), and peak work rate (r = 0.70,  < .001). CONCLUSIONS: HGS is strongly associated with total and segmental skeletal muscle mass, peak work rate, and peak oxygen consumption. Sex-based differences in handgrip strength values emerge in mid-teenage years in parallel to expected pubertal changes.