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Abstract Background The objective of our investigation was to better understand barriers to implementation of self-administered antigen screening testing for SARS-CoV-2 at institutions of higher education (IHE). Methods Using the Quidel QuickVue At-Home COVID-19 Test, 1347 IHE students and staff were asked to test twice weekly for seven weeks. We assessed seroconversion using baseline and endline serum specimens. Online surveys assessed acceptability. Results Participants reported 9971 self-administered antigen test results. Among participants who were not antibody positive at baseline, the median number of tests reported was eight. Among 324 participants seronegative at baseline, with endline antibody results and ≥ 1 self-administered antigen test results, there were five COVID-19 infections; only one was detected by self-administered antigen test (sensitivity = 20%). Acceptability of self-administered antigen tests was high. Conclusions Twice-weekly serial self-administered antigen testing in a low prevalence period had low utility in this investigation. Issues of testing fatigue will be important to address in future testing strategies.