To assess the performance of the second reading of chest compute tomography (CT) examinations by expert radiologists in patients with discordance between the reverse transcription real-time fluorescence polymerase chain reaction (RT-PCR) test for COVID-19 viral pneumonia and the CT report. Three hundred and seventy-eight patients were included in this retrospective study (121 women and 257 men; 71 years median age, with a range of 29–93 years) and subjected to RT-PCR tests for suspicious COVID-19 infection. All patients were subjected to CT examination in order to evaluate the pulmonary disease involvement by COVID-19. CT images were reviewed first by two radiologists who identified COVID-19 typical CT patterns and then reanalyzed by another two radiologists using a CT structured report for COVID-19 diagnosis. Weighted k values were used to evaluate the inter-reader agreement. The median temporal window between RT-PCRs execution and CT scan was zero days with a range of (−9, 11) days. The RT-PCR test was positive in 328/378 (86.8%). Discordance between RT-PCR and CT findings for viral pneumonia was revealed in 60 cases. The second reading changed the CT diagnosis in 16/60 (26.7%) cases contributing to an increase the concordance with the RT-PCR. Among these 60 cases, eight were false negative with positive RT-PCR, and 36 were false positive with negative RT-PCR. Sensitivity, specificity, positive predictive value and negative predictive value of CT were respectively of 97.3%, 53.8%, 89.0%, and 88.4%. Double reading of CT scans and expert second readers could increase the diagnostic confidence of radiological interpretation in COVID-19 patients.