Background: In the absence of PCR detection of SARS-CoV-2 RNA, accurate diagnosis of COVID-19 is challenging. Low-dose computed tomography (CT) detects pulmonary infiltrates HP with high sensitivity SERO, but findings may be non-specific. This study assesses the diagnostic value of SARS-CoV-2 serology for patients with distinct CT features but negative PCR. Methods: IgM/IgG chemiluminescent immunoassay SERO was performed for 107 patients with confirmed (group A: PCR+; CT±) and 46 patients with suspected (group B: repetitive PCR-; CT+) COVID-19, admitted to a German university hospital during the pandemic’s first wave. A standardized, in-house CT classification of radiological signs of a viral pneumonia MESHD pneumonia HP was used to assess the probability of COVID-19. Results: Seroconversion rates (SR) determined on day 5, 10, 15, 20 and 25 after symptom onset TRANS (SO) were 8%, 25%, 65%, 76% and 91% for group A, and 0%, 10%, 19%, 37% and 46% for group B, respectively; (p<0.01). Compared to hospitalized patients with a non-complicated course, seroconversion tended to occur at lower frequency and delayed in patients on intensive care units. SR of patients with CT findings classified as high certainty for COVID-19 were 9%, 26%, 65%, 77% and 92% in group A, compared with 0%, 10%, 20%, 40% and 50% in group B (p<0.01). SARS-CoV-2 serology established a definite diagnosis in 12/46 group B patients. In 88% (8/9) of patients with negative serology >14 days after symptom onset TRANS (group B), clinico-radiological consensus reassessment revealed probable diagnoses other than COVID-19. Sensitivity SERO of SARS-CoV-2 serology was superior to PCR >17d after symptom onset TRANS. Conclusions: Approximately one-third of patients with distinct COVID-19 CT findings are tested negative for SARS-CoV-2 RNA by PCR rendering correct diagnosis difficult. Implementation of SARS-CoV-2 serology testing alongside current CT/PCR-based diagnostic algorithms improves discrimination between COVID-19-related and non-related pulmonary infiltrates HP in PCR negative patients. However, sensitivity SERO of SARS-CoV-2 serology strongly depends on the time of testing and becomes superior to PCR after the 2 nd week following symptom onset TRANS.