Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). This study aimed to determine if SARS-CoV-2 RNA in serum at admission correlated with clinical outcome in COVID-19. Methods COVID-19 patients admitted to the infectious diseases department of a tertiary level Swedish hospital and sampled for SARS-CoV-2 RNA in serum at admission during 10 April to 30 June 2020 were included. Primary outcomes were day 28 all-cause mortality and progress to critical disease. Results The cohort (N = 167) consisted of 106 SARS-CoV-2 RNA serum-negative and 61 serum-positive patients. Median sampling time for initial SARS-CoV-2 in serum was 1 day (interquartile range IQR, 1–2 days) after admission, corresponding to day 10 (IQR, 8–12) after symptom onset. Median age was 53 years (IQR, 44–67 years) and 63 years (IQR, 52–74 years) for the serum–negative and -positive patients, respectively. In the serum-negative and -positive groups, 3 of 106 and 15 of 61 patients died, respectively. The hazard ratios for critical disease and all-cause mortality were 7.2 (95% confidence interval CI, 3.0–17) and 8.6 (95% CI, 2.4–30), respectively, for patients with serum–positive compared to serum–negative results. Conclusions SARS-CoV-2 RNA in serum at hospital admission indicates a high risk of progression to critical disease and death. Severe acute respiratory syndrome coronavirus 2 RNA in serum at admission was associated with a 7-fold increased risk of critical disease and an 8-fold increased risk of death in a cohort of 167 patients hospitalized for coronavirus disease 2019.