The RX's success continued in its eighth year of production, combining a smooth and responsive ride and fine Lexus details within a desirable SUV exterior. This was the final production year for the 330 before the RX line underwent a third makeover for 2007.

The RX 330 remained largely unchanged between 2005 and 2006, with the exception of minor interior details and extended options. New options included  a six-disc CD changer, dynamic laser cruise control, a rear back-up camera, rear seat entertainment system, adjustable front seat heaters, rain-sensing wipers, a towing package, roof rails, and 18-inch aluminum alloy wheels.  Lexus also introduced the hybrid RX 400h for 2006.

The 330 featured the same 3.3-liter V6 that powered the previous year's version, making 230 horsepower and pushing the RX from 0 to 60 mph in just under 9 seconds. Fuel economy continued to be acceptable at 19/25 mpg. While many drivers were pleased with the five-speed transmission's smoothness at higher speeds, those who drive more in the city were disappointed with the uneven shifting in the lower gears.