Police in New York City have launched a manhunt for a gunman who killed UnitedHealthcare’s CEO on Wednesday outside a Manhattan hotel where the health insurer was holding its investor conference.

Brian Thompson, 50, was shot around 6.45am as he walked alone to the New York Hilton Midtown from a nearby hotel, police said.

The shooter appeared to be “lying in wait for several minutes” before approaching Thompson from behind and opening fire, New York City Police Commissioner Jessica Tisch said.

Police had not yet established a motive.

“Many people passed the suspect, but he appeared to wait for his intended target,” Tisch said, adding that the shooting "does not appear to be a random act of violence.”

Surveillance video reviewed by investigators shows someone emerging from behind a parked car, pointing a gun at Thompson’s back, then firing multiple times from several feet away.

The gunman continues firing, interrupted by a brief gun jam, as Thompson stumbles forward and falls to the pavement. He then walks past Thompson and out of the frame.

“From watching the video, it does seem that he’s proficient in the use of firearms as he was able to clear the malfunctions pretty quickly,” NYPD Chief of Detectives Joseph Kenny said.

Thompson was shot at least once in the back and once in the calf, Tisch said.

The shooter, who wore a jacket, face mask and large backpack, fled through midtown on foot before pedalling an electric bike into Central Park a few blocks away, police said.

The assailant remained at large Wednesday afternoon, sparking a search that included police drones, helicopters and dogs. (AP)