Methods and systems for setting up inspection of a specimen with design and noise based care areas are provided. One system includes one or more computer subsystems configured for generating a design-based care area for a specimen. The computer subsystem(s) are also configured for determining one or more output attributes for multiple instances of the care area on the specimen, and the one or more output attributes are determined from output generated by an output acquisition subsystem for the multiple instances. The computer subsystem(s) are further configured for separating the multiple instances of the care area on the specimen into different care area sub-groups such that the different care area sub-groups have statistically different values of the output attribute(s) and selecting a parameter of an inspection recipe for the specimen based on the different care area sub-groups.