The second-generation RS 6, later called the Audi RS 6 5.0 TFSI quattro (Typ 4F) was based on the Volkswagen Group C6 automobile platform and was launched in September 2007 at the Frankfurt Motor Show. With factory production starting in April 2008, it was available in Europe from the same date, and began to be exported elsewhere in 2009. The total production run of the C6 RS 6 was 8,000 units, with 6,500 of these being Avants and the remainder saloons. The RS 6 was not available in North America, leaving the Audi S6 as the top performing trim there. (The unpopularity of wagons made it unlikely that the RS 6 Avant would be imported, and although it had been rumoured that the RS 6 sedan would be offered in the United States, nothing came of this as the RS 6 importer could not clear US regulations). Production of the C6 RS 6 ended in the third quarter of 2010.

The RS 6's 5.0L V10 biturbo engine produced 426 kilowatts (579 PS; 571 bhp) at 6,250 to 6,700 rpm, and 650 newton metres (479 lbf·ft) of torque from 1,500 to 6,250 rpm, 52 kW (71 PS; 70 bhp) and 150 N·m (111 lb·ft) more than BMW's 5.0L V10 engine. As of January 2010, the RS6 was Audi's single most powerful car ever, and positioned the car ahead of its closest competitors, the BMW M5 and the Mercedes-Benz E63 AMG in terms of engine output, both of which have naturally aspirated engines. However the estimated price of the RS 6 sedan in 2010 was $160,000 USD (another source quotes $126,000 USD in 2009, making the RS 6 perhaps too expensive for the United States market) which set it apart from the performance variants of other executive cars: the MRSP of BMW M5's was $85,700 USD, of Mercedes-Benz E63 AMG's was $87,700 USD, and of Audi's own S6 was $78,025 USD.

Official performance figures for the Avant: 4.6 seconds for the 0-100 kilometres per hour (62.1 mph) sprint, 12.7 seconds 0-200 km/h (124.3 mph), and top speed is electronically limited to 250 km/h (155.3 mph), with a factory option to de-restrict the top speed to 274 km/h (170.3 mph). In standard form, CO₂ emissions are rated at 333 g/km. The saloon reaches 0-100 km/h (62.1 mph) in 4.5 seconds.