PURPOSE The benefit of routine pre-emptive screening for severe acute respiratory syndrome coronavirus 2 infections in patients with cancer before cancer-directed therapies is unclear. Herein, we characterize the outcomes of a cohort of patients with cancer who were diagnosed with COVID-19 by routine screening (RS) in comparison with those diagnosed on the basis of clinical suspicion or exposure history (nonroutine screening [NRS]). METHODS A multisite prospective observational study was conducted at three major and five satellite campuses of the Mayo Clinic Cancer Center between March 18 and July 31, 2020. The primary outcome was COVID-19–related hospital admission. Secondary outcomes included intensive care unit admissions and all-cause mortality. RESULTS Five thousand four hundred fifty-two patients underwent RS in the outpatient setting only, and 44 (0.81%) were diagnosed with COVID-19. RS detected 19 additional patients from the scheduled inpatient admissions for surgical or interventional procedures or inpatient chemotherapy. One hundred sixty-one patients were diagnosed with COVID-19 on the basis of NRS. COVID-19–related hospitalization rate (17.5% v 26.7%; P 5 .14), intensive care unit admission (1.6% v 5.6%; P 5 .19), and mortality (4.8% v 3.7%; P 5 .72) were not significantly different between the RS and NRS groups. In the multivariable analysis, age $ 60 years (odds ratio, 4.4; P 5 .023) and an absolute lymphocyte count # 1.4 3 109/L (odds ratio, 9.2; P 5 .002) were independent predictors of COVID-19–related hospital admission. CONCLUSION The COVID-19 positivity rate was low on the basis of RS. Comparing the hospital admission and mortality outcomes with the NRS cohort, there were no significant differences. The value of routine pre-emptive screening of asymptomatic patients with cancer for COVID-19 remains low.