The second-generation Sprinter was introduced in Europe in 2006. It was voted Van of the Year for 2007 and again in 2008 by Professional Van and Light Truck Magazine.  Also known as the NCV3 or New Concept Van 3, the second generation Sprinter appeared in Europe and in other countries as the 2006 model year. North America received its own NCV3 for the 2007 model year.

The U.S. cargo version of the 906 NCV3 came in two wheelbase options (144", 170"), two roof heights (standard 60.6", high 72.4"), three lengths (Short 233.3", Standard 274.2, Extended 289.8"), and two weight classes (2500, 3500). 3500 models had the option of dual rear wheels or extra-wide "super single" wheels in some, but not all, markets. Neither the 128" wheelbase nor the rear super single tires were available in the U.S. market. The U.S. cargo version was reassembled from kits in an assembly plant located in Ladson, South Carolina, while the passenger models were imported directly from Germany. The second-generation 906 was produced in Argentina only for export markets—except Mercosur markets (Brazil, Uruguay and Paraguay)—from 2007 until 2010, but in 2011, announced new production of the second generation in the Centro Industrial J. Manuel Fangio, in Buenos Aires with the brand-new OM 651 engine (also locally made) and exported to the rest of South America (including Mercosur markets). Since 2012, it has been manufactured for the Mercosur and 40 other countries. 70% of its production is exported.