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<h4>Background</h4>We examined the determinants of adolescents' Health-Related Quality of Life (HRQoL) and psychological distress (self-reported and parent-reported) during the COVID-19 pandemic, using a random sample of the population of Geneva, Switzerland.<h4>Methods</h4>Data was drawn from participants aged 14-17 years, who participated with their families to a serosurvey conducted in November and December 2020. Adolescents' HRQoL was evaluated using the validated adolescent-reported KIDSCREEN-10 and parent-reported KINDL® scales. Psychological distress was assessed with self-reported sadness and loneliness, and using the KINDL® emotional well-being scale. Using generalized estimating equations, we examined the role of socio-demographic, family and behavioural characteristics in influencing adolescents' mental health status and wellbeing.<h4>Results</h4>Among 240 adolescents, 11% had a low HRQoL, 35% reported sadness and 23% reported loneliness. Based on parents' perception, 12% of the adolescents had a low HRQoL and 16% a low emotional well-being. Being a girl (aOR = 3.20; 95%CI: 1.67-6.16), increased time on social media (aOR = 2.07; 95%CI: 1.08-3.97), parents' average to poor mood (aOR = 2.62; 95%CI: 1.10-6.23) and average to poor household financial situation (aOR = 2.31; IC95%: 1.01-6.10) were associated with an increased risk of sadness. Mismatches between adolescents' and their parents' perception of HRQoL were more likely for girls (aOR = 2.88; 95%CI: 1.54-5.41) and in households with lower family well-being (aOR = 0.91; 95%CI: 0.86-0.96).<h4>Conclusions</h4>A meaningful proportion of adolescents experienced low well-being during the second wave of COVID-19, and average well-being was lower than pre-pandemic estimates. Adolescents living in underprivileged or distressed families seemed particularly affected. Monitoring is necessary to evaluate the long-term effects of the pandemic on adolescents.