When Operation Barbarossa started, the IAR 80 equipped Esc. 41, 59 and 60 of Grupul 8 Vanatoare, part of the Grupul Aerien de Lupta (GAL), that were tasked to support the Romanian 3rd and 4th Armies deployed at the southern flank of the Eastern Front. Grupul 8 was the only unit assigned a pure fighter role, while Grupul 5 and 'Grupul 7, equipped with German superior aircraft (Heinkel He 112s and Messerschmitt Bf 109s) were employed primarily as fighter-bombers and bomber escorts.
On 22 June 1941, during the first day of the offensive, the IAR 80 patrols had their baptism of fire, achieving a single aerial victory (claimed by Sublocotenent aviator Ioan Miháilescu of Esc 60 van, a future ace) during four separate air combats. However, at least four IARs force landed with battle damage, while another two suffered engine trouble. By the end of 1941, 20 IAR 80/81s had been lost in combat in accidents. During 1942 the Romanian aviation industry reached its highest output so that the Royal Romanian Air Force could be re-equipped as follows: Esc. 47, 48 and 52 (Grupul Vanatoare), Esc. 43, 44 and 50 (Grupul 3 Vanatorae) and Esc. 41, 42 and 60 (Grupul 8 Vanatoare) received the new IAR 80A. Esc. 53 also replaced its Hurricanes with the IAR 80A, while Grupul 6 Bopi re-equipped with the IAR 81.
In June 1942, the operational IAR fighter forces on the Eastern front, combined into the Flotilla 2 Vanatoare consisted of Grupul 8 Vanatoare, commanded by Cdr. Lt Col E. Pirvulescu, and included Escadrila 41, Escadrila 42 and Escadrila 60 with 12 IAR 80As each. Grupul 8 moved at the end of September, to Karpovka, joining Grupul 7, equipped with Bf 109s. On 12 and 13 December, Grupul 6 used its IAR 81s to support the German counterattack by the Panzergruppe Hoth of the Heeresgruppe Don, from Kotelnikovo towards Stalingrad. In the summer of 1943 the FARR's IAR-80s were transferred to Romania for air defense duties,where they were used in combat against the USAAF. USAAF attacks were directed at the oil refinery installation at Ploieşti, in particular. On 1 August 1943 the IAR 80 faced for the first time the B-24 Liberator. They were 178 B-24 from 9th USAAF, part of the Operation Tidal Wave. The IAR 80Bs of Escadrila 61 and 62 of Grupul 6 vânátoare, as well as IAR 80Cs from the newly formed Escadrila 45 of Grupul 4 vânátoare, together with the Bf 109Gs from Esc. 53 and Bf 110s from the Romanian night fighter squadron, dived on the low-flying, four engined bombers, belonging to five USAAF bomber groups (the 44th, 93rd, 98th, 376th and 389th). The Americans lost – in combat or on the way back – 51 bombers. Only 89 reached their bases, of which only 31 were serviceable for a mission the next day. The Romanians pilots claimed 25 certain and probable victories for just two losses, one IAR 80 B and one Bf 110C. According to Romanian statistics, IARs and Messerschmitts were confirmed as having shot down ten B-24s, with two probables.