Interferons are a major part of the anti-viral innate defense system. Successful pathogens, including 22 the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), need to overcome these 23 defenses to establish an infection. Early induction of interferons (IFNs) protects against severe 24 coronavirus disease 2019 (COVID-19). In line with this, SARS-CoV-2 is inhibited by IFNs in 25 vitro, and IFN-based therapies against COVID-19 are investigated in clinical trials. However, 26 SARS-CoV-2 continues to adapt to the human population resulting in the emergence of variants 27 characterized by increased transmission fitness and/or decreased sensitivity to preventive or 28 therapeutic measures. It has been suggested that the efficient spread of these so-called “Variants 29 of Concern” (VOCs) may also involve reduced sensitivity to IFNs. Here, we examined whether 30 the four current VOCs (Alpha, Beta, Gamma and Delta) differ in replication efficiency or IFN 31 sensitivity from an early isolate of SARS-CoV-2. All viruses replicated in a human lung cell line 32 and in iPSC-derived alveolar type II cells (iAT2). The Delta variant showed accelerated replication 33 kinetics and higher infectious virus production compared to the early 2020 isolate. Replication of 34 all SARS-CoV-2 VOCs was reduced in the presence of exogenous type I, II and III IFNs. On 35 average, the Alpha variant was the least susceptible to IFNs and the Alpha, Beta and Gamma 36 variants show increased resistance against type III IFN. Although the Delta variant has 37 outcompeted all other variants in humans it remained as sensitive to IFNs as an early 2020 SARS38 CoV-2 isolate. This suggests that increased replication fitness rather than IFN resistance may be a 39 reason for its dominance. Our results may help to understand changes in innate immune 40 susceptibility of VOCs, and inform clinical trials exploring IFN-based COVID-19 therapies.