Background: The purpose of this study was to investigate prevalence of self-reported symptom burden during the acute phase of SARS-CoV-2 infection and associated factors including sex differences. Methods: All Danish adolescents aged 15–18 years with laboratory confirmed SARS-CoV-2 infection between January 2020 and July 2021 were invited to participate. A survey covered the initial four weeks of SARS-CoV-2 infection and included questions regarding 17 symptoms associated with acute COVID-19, symptom burden and medical history. Statistical analyses included descriptive statistics and logistic regression. Findings: A total of 24,315 adolescents with SARS-CoV-2 infection were invited and 6630 (27.3%) completed the questionnaire. The median age was 17.6 years, and 58.4% (n = 3873) were female. No symptoms were reported by 33.8% (n = 2241), mild perceived symptom burden by 57.2%(n = 3775), and severe symptom burden by 9.0 % (n = 594). Two thirds (n = 2999) of the symptomatic participants reported a symptom duration of 1–10 days. The most prevalent symptoms included headaches 39.2% (n = 2597), a reduced sense of smell 36.2% (n = 2398), cough 31.6% (n = 2093), sore throat 31.1% (n = 2063), and a reduced sense of taste 31.1% (n = 2062). Adolescents at the age of 18 years had higher odds of reporting ≥6 symptoms OR1.47 (95%CI, 1.23–1.76), p < 0.0001 and adolescents 18+ years old had higher odds of reporting a severe symptom burden OR1.98 (95%CI, 1.43–2.73) compared to the 15years old adolescents. A history of OCD/anxiety/depression was associated with reporting ≥6 symptoms OR 1.67 (95%CI, 1.34–2.09), p < 0.0001 and a history of allergy and OCD/anxiety/depression reporting severe symptom burden OR 1.64 (95%CI, 1.35–1.99), p < 0.0001 and OR 1.75 (95%CI, 1.28–2.36), p = 0.0004. Females reported more symptoms than males; median of three (IQR 0–6) vs. a median of two (IQR 0–4) symptoms, p < 0.0001. Interpretation: Two in three experienced symptoms and the majority reported mild symptom burden. Headache, a reduced sense of smell and taste, cough and sore throat were most common. Female sex, asthma and previous Epstein-Barr virus were associated with more symptoms and higher symptom burden. Funding: The study was funded by the AP Møller Foundation. The research was investigator initiated. The study funder played no role in the study.