Methods and systems for inspection of a wafer or setting up an inspection process are provided. One method for inspection of a wafer includes detecting first and second sets of defects on the wafer by performing different scans of the wafer with different focus offsets. The method also includes comparing results of the different scans for a defect of the first set and a defect of the second set that are detected at approximately the same location on the wafer. The method further includes determining if the defect of the first and second sets is a defect of an underlying layer or an uppermost layer formed on the wafer based on results of the comparing step.