Monoclonal antibody therapy was granted emergency use authorization for high-risk patients with mild-moderate coronavirus disease 2019 (COVID-19) illness. The optimal time for mAb infusion is yet to be determined. We performed a single center, retrospective, case-control risk factor analysis in adult outpatients with mild-moderate COVID-19 illness who received mAb therapy from December 2020-December 2021. Patients requiring an Emergency Department (ED) visit or inpatient admission due to COVID-19 symptoms within 28 days following mAb infusion were considered cases with progressive disease and were compared to control patients who received mAb therapy without progressive disease. Risk factors independently associated with disease progression were determined using multivariable logistic regression. A total of 1,156 (77.4%) of 1,494 patients who received mAb therapy for mild-moderate COVID-19 illness met inclusion criteria and were included in the analysis. Sixty-five (5.6%) patients had disease progression with a COVID-19-related ED encounter or inpatient admission despite mAb administration. Twenty-two (33.8%) received mAb infusion within 5 days of symptom onset. In univariate analysis, older age, Elixhauser comorbidity index, receiving bamlanivimab, and delayed mAb administration after 5 days of symptoms were associated with disease progression. In multivariate analysis, Elixhauser comorbidity index and delayed mAb administration after 5 days of symptoms were independently associated with increased risk of disease progression. Our study was able to demonstrate that both a higher Elixhauser comorbidity index and delayed mAb administration after 5 days of symptoms increases risk of COVID-19 disease progression resulting in either an ED encounter or inpatient admission.