BACKGROUND: Allergen immunotherapy (AIT) is safe and effective but is typically administered under strict clinic observation to mitigate the risk of a systemic reaction to immunotherapy (SRIT). However, in the setting of the global coronavirus disease 2019 pandemic, alternative care models should be explored. OBJECTIVE: To evaluate the cost-effectiveness of home immunotherapy self-administration (HITSA) in a highly idealized circumstance for provision of maintenance AIT in a shelter-in-place or other scenarios of unforeseen reduction in nonessential medical services. METHODS: Markov modeling was used to compare in-office clinic AIT in selected patients using cohort analysis and microsimulation from the societal and health care perspectives. RESULTS: Assuming similar SRIT rates, HITSA was found to be a cost-effective option with an incremental cost-effectiveness ratio of $44,554/quality-adjusted life-year when considering both incremental epinephrine autoinjector costs and coronavirus disease 2019 risks. Excluding epinephrine autoinjector costs, HISTA dominated other options. However, outside of pandemic considerations, HITSA was not cost-effective (incremental cost-effectiveness ratio, $198,877,286) at annual epinephrine autoinjector costs above $287. As the incremental HITSA SRIT rate increased above 15%, clinic AIT was the most cost-effective strategy. Excluding both pandemic risks and risk of motor vehicle accident fatality from round-trip clinic transit, clinic AIT dominated other strategies. Clinic AIT was the more cost-effective option at very high fatality relative risk for HITSA or at very low annual risk of contracting coronavirus disease 2019. CONCLUSIONS: Under idealized assumptions HITSA can be a safe and cost-effective option during a global pandemic in appropriately selected patients provided home rates of SRIT remain stable.