The C.205 entered production only five months after its maiden flight and began reaching front line units in February 1943. At the end of April, the 1° Stormo, based in Pantelleria, is the first unit to enter action with the C.205, on Mediterranean, escorting maritime and aerial convoys to and from Tunisia. During their first sortie, 22 C.205 clashed with very good results against more numerous formations of Curtiss P.40 and Supermarine Spitfires. During the next few months, C.205s of the Regia Aeronautica were involved in several major engagements with some of the 4,000 Allied aircraft that were stationed in the Mediterranean at that time. At the end of May, because of the vulnerability of Pantelleria, the 1° Stormo was moved to Sigonella airfield, in Sicily, and on the minor airstrip of Finocchiara, 15 km South-East of Ragusa. On June 8, 1943, 15 C.205 of 1° Stormo escorted three torpedo-bombers attacking Allied ships which were shelling Pantelleria's defenses. At the end of June, the Stormo had no more serviceable Veltros. On 24 June, 1° Stormo left Sicily for Osoppo first, and Ronchi dei Legionari later, and was replaced by 4° Stormo. Few pilots returned to Udine, while the remaining aircraft joined other units. 4° Stormo, that had left Africa in January 1943, was re-equipped with Macchi C.202s and C.205s on the airfields of Campoformido (10° Gruppo) and Bresso (9° Gruppo). It was then moved on Rome-Ciampino airport. On 9 July 1943 (the eve of the Allied invasion of Sicily), 4° Stormo was based in the Catania plain, with a complement of 10 Veltros and 38 Folgores (no Italian unit was equipped with Veltros alone). Later it received a batch of a further 10 C.205s. The Italian pilots flew as many as six sorties per day, but on the 14th of July, with the first Allied paratroopers landing on the Catania plain, 4° Stormo was forced to retreat to Crotone airfield in Calabria after setting fire to four or five damaged C.205s that could not be repaired in time.
51° Stormo fought with some success over Sardinia, (apart from the battle of 2 August) but sustained many losses, especially at the end of July and the beginning of August. 3° Stormo C.T., commanded by Tenente Colonnello Tito Falconi, also had the chance to use the "Veltro" in combat. At the time it was based on Cerveteri airstrip with the task to defend Rome, 83a, 85a and 95a Squadriglia, 18° Gruppo (of 3° Stormo) all received a number of C.205s. Commander Falconi assigned them to the most eminent pilots: Sergente Maggiore Luigi Gorrini, Tenente Franco Bordoni-Bisleri and Maresciallo Guido Fibbia. The 3° Stormo used the new type effectvely to intercept American bombers and fighters in the sky of Latium. "The Macchi fighter possessed some excellent qualities, and the Italian pilots made optimum use of the aircraft which had a maximum speed of 644 km/h (400 mph)." One of the greatest British fighter pilots of World War II, Group Captain Duncan-Smith DSO DFC respected both the Macchi and the Italian airmen:
- In general the standard of flying of the Italian pilots was very high indeed, and in encounters with Macchi 205s particularly we were up against aircraft that could turn and dog-fight with our Spitfires extremely well.
Like its predecessors, the first Veltros were insufficiently armed, but the aircraft often performed well in combat. Guido Carestiato said about the C.205, that it was the "best Italian fighter that he knew" and many pilots like the C.205 "ace" Luigi Gorrini, scored 19 or 24 victories (in return, he was downed four or five times). Gorrini claimed 12 victories in July 1943 and several of them were with the Veltro.