<h3>Abstract</h3> <h3>Purpose</h3> Our objective was to assess adolescent’s Health-Related Quality of Life (HRQoL) and psychological distress, from their own and their parents’ perspective, and to examine associated risk factors during the COVID-19 pandemic in Geneva, Switzerland. <h3>Methods</h3> A random sample of adolescents, aged 14-17 years, and their families was invited to a serosurvey in November and December 2020. Adolescents’ HRQoL was evaluated using the validated adolescent-reported KIDSCREEN-10 and parent-reported KINDL<sup>®</sup> scales. Psychological distress was assessed with self-reported sadness and loneliness, and using the KINDL<sup>®</sup> emotional well-being scale. Risk factors for adolescents’ low HRQoL and psychological distress were identified using generalized estimating equations and both adolescents’ and their parents’ perceptions were compared. <h3>Results</h3> 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=3.29; 95%CI: 1.64-6.57), increased time on social media (aOR=2.05; 95%CI: 1.08-3.88), parents’ <i>average to poor</i> mood (aOR=2.81; 95%CI: 1.21-6.56) and <i>average to poor</i> household financial situation (aOR=2.30; 95%CI: 1.00-5.29) were associated with an increased risk of sadness. Mismatches between adolescents’ and their parents’ perception of HRQoL were more likely for girls (aOR<b>=</b>2.88; 95%CI: 1.54-5.41) and in households with lower family well-being (aOR<b>=</b>0.91; 95%CI: 0.86-0.96). <h3>Conclusion</h3> A meaningful proportion of adolescents experienced low well-being during the second wave of COVID-19. Adolescents living in underprivileged or distressed families seemed particularly affected. Monitoring is necessary to evaluate the long-term effects of the pandemic on adolescents. <h3>Implications and Contribution</h3> This study describes the psychological well-being of a population-based sample of adolescents in Geneva, Switzerland amid the COVID-19 pandemic, and identifies adolescents at risk of distress. This study provides further insight by comparing adolescents’ well-being as reported by themselves and their parents.