BACKGROUND Mass testing for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been an important tool to limit the spread of infection in society during the coronavirus disease 19 (COVID-19) pandemic. Proper upper respiratory specimen collection is the most critical step in the diagnosis of the SARS-CoV-2 virus in public settings. An oropharyngeal swab (OPS) specimen is the preferred sample in many countries, either alone or combined with nasal swab. However, there is great variability in the diagnostic accuracy for OPS with a 95% confidence interval from 52-100% reported in systematic reviews. Many of the previous studies performing OPS also lack a detailed description of the OPS sampling technique, which makes it difficult to compare the different diagnostic accuracy results. Some studies perform an oropharyngeal sample by only collecting specimens from the posterior oropharyngeal wall while others also include a swab of the palatine tonsils for SARS-CoV-2 testing. However, studies suggest that the palatine tonsils could have a tissue tropism for SARS-CoV-2 which may improve the SARS-CoV-2 detection during sampling. This may explain the variation of sensitivity reported, but no clinical studies have explored the differences between the two sample techniques. OBJECTIVE The objective of this study is to examine the sensitivity of an OPS sample, including the palatine tonsils, compared to only swabbing the posterior oropharyngeal wall in molecular detection of SARS-CoV-2. METHODS We will conduct a randomized, controlled study to compare the molecular detection rate of SARS-CoV-2 by an OPS performed from the posterior oropharyngeal wall and the palatine tonsils (intervention group) or the posterior oropharyngeal wall only (control group). Participants will be randomized in a 1:1 ratio. All participants fill out a baseline questionnaire on the day of the test examining their reason for being tested, symptoms etc. and a follow up questionnaire three months later exploring the course of illness. RESULTS A total of 2361 participants we enrolled in this study between November 10th 2022 and December 31st 2022 and data from follow up questionnaires are expected to be collected until May 1st 2023. CONCLUSIONS This randomized clinical trial will provide us with information about whether oropharyngeal swabs including specimens from the palatine tonsils will improve the diagnostic sensitivity for SARS-CoV-2 molecular detection. These results can, therefore, be used to improve future testing recommendations as well as it will provide additional information about the tissue tropism for SARS-CoV-2. CLINICALTRIAL The protocol was registered with the ClinicalTrials.gov database (NCT05611203).