Mears' early Indy car success attracted the attention of Brabham Formula One team boss Bernie Ecclestone, who invited Mears to participate in two tests driving the Brabham BT49, first at France's Paul Richard circuit, and California's Riverside International Raceway. In France, Mears was within a half-second of Brabham team driver Nelson Piquet's fastest time and posted faster laps than Piquet at Riverside. After the tests, Ecclestone presented Mears a contract offer to join the F1 team, but Mears stayed with Team Penske.

Team Penske introduced the PC9B for the 1981 season, an enhancement from the PC9 chassis. Electrical troubles forced Mears to use his backup car on the second day of "500" qualifying, and he qualified 25th. In the race, Mears moved up through the field before a routine pit stop ended with a large methanol fire, with Mears suffering burns to his face and eyelids.

He missed the next race at Milwaukee as he recovered, but returned a month after the fire, winning twin 125-mile races at Atlanta Motor Speedway. Later in the season, Mears won at Riverside and then clinched his second CART Championship by winning three races in a row.