The first three prototypes and five pre-production vehicles formed the Luft-Transportstaffel (See) 222.
In October 1943 a Bv 222 shot down a Lancaster over the Atlantic.
The Bv 222 was used for transportation in the Mediterranean and by the end of 1942 carried 1,377 tons of cargo, 17,000 troops, and 2,400 casualties. All seven Bv 222s carried a total of 3,496 tons of cargo, 37,500 troops, and 5,169 wounded in 1942 on all fronts.
It was found that the Bv 222 was rather vulnerable to attack after two were shot down and one damaged while in use in the Mediterranean. After this most flights were conducted at night. The flights were often escorted by two Me 110s.
The Bv 222s were then sent to France to be used as reconnaissance planes. They weren't very successful and were returned to being transports.
Seven survived the war and two (Bv 222 C-011 and Bv 222 C-013) were flown to the United States for evaluation. Bv 222 C-012 was captured by the British in Norway.