Some things that affect fuel economy are driving conditions, i.e..,
stop-and-go, driving on hills, highway, etc.; driving style; engine and
transmission; payload; and vehicle weight.

In general, larger cars have larger engines to pull the weight of the larger
car.

EPA fuel economy estimates may or may not reflect an individual driver's
results due to the many variables, but they are good for comparing between
different vehicles.  Lexus offers only one engine choice for a particular
series but Mercedes offers some vehicles with engine choices - for example,
the E-class can be had with 6 or 8 cylinder engines.  If most of the driving
is in an urban environment and the driver has a gentle foot, the smaller
engine will probably offer better fuel economy than a larger engine.

As far as the difference in cost, the EPA estimates will show relative
differences in fuel cost.

I think another thing to consider is gas requirements.  The LS430 needs
premium, so that will run the cost up too.

MY SC400 (8 cyl) gets better mileage than my SC300 (6 cyl)

Hi Anna, even with today's gas prices, your major concern when
purchasing a vehicle is to look at the estimated annual depreciation of
that vehicle.  A Lexus will depreciate far less than a Mercedes or GM
product.  That said, remember, a powerful engine is an open invitation
to speeding and jack rabbit starts, hence you should also factor the
cost of police tickets when considering a V8 instead of a Six.  My
Lexus Six has already spares me a couple of speeding tickets
annually!!!!!!!!!!!!!1