The rear styling is similar to the Mercedes-Benz Maybach – the larger saloon from Daimler AG's other flagship brand, which was presented to the public in 1997.

[7] Inside, the W221's interior is also significantly different from the preceding model, even more dominated by leather, wood and metal.

Where the W220 still had a fair amount of plastic fascias and switches, the W221 has replaced most of these by more luxurious materials such as wood, leather and metal.

The interior features an instrument cluster with two large flat panel screens, one for the hard disk based COMAND system which includes the navigation screen and one replacing the analog speedometer by a graphical representation of it, which can display a range of additional information and can also be replaced by the Night View Assist display.

Below the vents are metal tab switches with a black field behind them, to control the HVAC system (these functions are all also accessible via the COMAND system, which also offers access to some additional HVAC functions, such as foot-well temperature settings and air flow control).

Below the HVAC button section is a panel that opens to give access to the DVD changer which also includes a CompactFlash card reader.

The S-Class is available in short-wheelbase form, except in the US,[8] Mexico,[9] Russia, China and Indonesia,[10] where all models are long-wheelbase.

The W221 also contains many other safety features, including front and rear crumple zones, eight dual-stage air bags, anti-lock brakes (ABS), collapsible steering column, and traction control.

Changes include: on-demand electric hydraulic power steering pump, standstill decoupling for the 7G-TRONIC automatic transmission, and 17-inch light-alloy wheels with reduced rolling resistance tyres.

[26] The 3.5 liter V6 engine in the vehicle, combined with the hybrid system, develops 295 hp (220 kW) and 284 lb⋅ft (385 N⋅m) of torque.

[28] The V8 diesel was updated to offer more power (320 hp (239 kW))[citation needed] while reducing emissions and fuel consumption.

It resists military-standard small-arms projectiles and provides protection against fragments from hand grenades and other explosive charges.

Additional safety features include run-flat tyres, 90L self-sealing fuel tank and a fire-extinguishing system.

[29] Other features include Michelin PAX 245–700 R470 AC tires, optional emergency fresh-air system, pneumatic emergency control system for the power windows (operates independently of the on-board electronics), emergency boot opening facility, optional Panic Alarm System, rear camera, heated front windscreen and heated front windows, adjustable doorhold system for all four doors, rear doors that are pulled shut automatically over the last few millimetres, and rear electric roller blinds.

[32] The vehicles were delivered beginning in late 2008[33] (the first one in early part of the year for the inauguration of new Russian president Dmitry Medvedev).

[34] The S 63 AMG is powered by the Mercedes-Benz M156 V8 engine rated at 525 PS (386 kW; 518 hp) and 630 N⋅m (465 lbf⋅ft) of torque.

[35][36][37][38] It includes restyled front and rear bumpers and rocker panels, larger wheels, brakes, and tires, four exhaust pipes, modified and reprogrammed suspension for sport biased handling, and various interior changes.

The car is powered by a four-cylinder diesel engine which produces 150 kW (201 hp; 204 PS) and 500 N⋅m (369 lb⋅ft) of torque.

Models with 7G-TRONIC transmission include DIRECT SELECT, which allows 7G-TRONIC to be electronically controlled by touching the lever on the right-hand side of the steering column.

[56][57] As part of the W221 launch campaign, Mercedes-Benz Accessories GmbH introduced a series of 17 products under S-Class Collection, beginning in 2005–09.

Products include a wrist watch designed with Sindelfingen-based Design Centre, piqué polo shirt, cufflinks, pen, umbrella, key fob, mouse pads, pen cases, cigar set, note pad, wallet, and 1/43 S-Class scale model car.

[58] Mercedes-Benz Accessories GmbH also introduced a series of 1,200 units of S-Class vehicle freight train.