A Pentagon spokesperson confirmed the incident to Sputnik, but said the aircraft was not carrying nuclear material.
"I can confirm there was an V-22 crash in Glamis, California. There was no nuclear material on board. We don't have any additional information," the spokesperson said on Wednesday. They could not confirm reports of casualties.
Four of the five crew are reportedly dead, with the fifth person unaccounted for, according to local news.
The crash was reported in Imperial County near the town of Glamis, about 20 miles north of the US-Mexico border and 23 miles west of the Arizona border.
Naval Air Facility El Centro, located about 36 miles west of the crash vicinity, said on social media that the aircraft was from the 3rd Marine Aircraft Wing, based at Marine Corps Air Station Miramar, near San Diego.
The V-22 Osprey is an aircraft used by the US Navy and Marine Corps that can rotate its rotors to fly like a helicopter or like an aircraft. It is notorious for crashing, with the Department of the Navy delaying its adoption for years as problems were sorted out. A V-22 crash in March during drills in Norway killed four US Marines.