Aim: the objective of this study was to analyze the potential relationships between Health Related Quality of Life (HRQoL) with weight status, physical activity (PA) and fitness in Chilean adolescents in both, independent and combined analysis. Method: a sample of 767 participants (47.5% females) and aged between 12 and 18 (mean age 15.5) was employed. All measurements were carried out using selfreported instruments and Kidscreen-10, iPAQ and IFIS were used to assess HRQoL, PA and Fitness respectively. One factor ANOVA and linear regression models were applied to analyze associations between HRQoL, weight status, PA and fitness using age and sex as confounders. Results: body mass index, level of PA and fitness were independently associated with HRQoL in Chilean adolescents. However, the combined and adjusted by sex and age analysis of these associations showed that only the fitness was significantly related with HRQoL. Conclusion: general fitness is associated with HRQoL independently of sex, age, bodyweight status and level of PA. The relationship between nutritional status and weekly PA with HRQoL are mediated by sex, age and general fitness.