With the W108/W109 series of 1965, the range received V8 power for the first time. The W108 line launched with an initial lineup of straight-6 powered models. The unusual high-displacement 300 SEL 6.3 V8 model was based on this body type. The W108 line was larger than the Fintail models it replaced, and also eliminated the characteristic design feature of the previous model.

During this period, the designation SE was used for short wheelbase models including 250S, 250SE, and 300SE. Long wheelbase models (with more room particularly in the back) were designated SEL. Since the advent of the W108 series, the Mercedes S-Class has always included two wheelbase lengths. The more powerful 300SE and 300SEL models were the most luxurious versions of the W108 line, with burl walnut dashboards, automatic transmission, and power windows.

In 1968, the W108 line replaced the 250S and 250SE with the 280S and 280SE; the 300SE/SEL was later upgraded with a 3.5 litre V8 engine (in both the SE and SEL) and a 6.3 litre V8 engine (in the SEL model).