De Silvestro competed full-time in the IndyCar Series for HVM Racing for the 2010 season. On 22 May 2010, she qualified in the 22nd position for the 2010 Indianapolis 500. She finished the race in 14th position, and earned Indianapolis 500 Rookie of the Year honors. She suffered a burned right hand after a fiery crash at the Firestone 550 at Texas Motor Speedway on 5 June 2010. Her team strongly criticized IndyCar Series safety officials for their response to that accident. For the season, de Silvestro started 17 races, finished ten, and recorded two top-10 finishes, with a best finish of eighth at Mid-Ohio. She finished 19th overall in the series standings and was runner-up to Alex Lloyd for rookie of the year honors.