Shortly before 9am local time, police "received multiple emergency phone calls" from witnesses who saw the two aircraft collide about 50km north of Denver, the Boulder County Sheriff's Office said in a statement, Reuters reported.
When first responders came across the first crash site, both people onboard the plane were dead, police said.
The pilot of the second downed plane, who was the sole occupant, also was dead when emergency crews reached the wreckage, the sheriff's office said.
None of the victims were immediately identified.
The two aircraft were a Cessna 172 and a Sonex Xenos, the National Transportation Safety Board said in a statement, adding that investigators are probing what led up to the accident.
The Sonex Xenos is a lightweight aluminum, homebuilt aircraft, according to the company's website.
The Cessna 172 Skyhawk is a single-engine plane that seats four.
The Federal Aviation Administration said in a statement that the planes collided near the Vance Brand Airport, a general aviation airport in Longmont, Colorado.