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The two most desired properties for photo-detection using a strained-layer superlattice (SLS) are high native point defect (NPD) formation energies and absence of mid-gap levels. In this Letter we use first-principles calculations to study the formation energies of NPDs. First we validate the numerical method by comparing the calculated defect formation energies with measured values reported in the literature. Then we calculate the formation energy of various NPDs in a number of InAs-GaSb SLS systems. From the calculated defect formation energies in SLS relative to that in constituent bulk material, the probability of defect presence in SLS can be inferred if we know the growth conditions of SLS with respect to those of the bulk material. Since the defects with much higher formation energy in SLS will be difficult to form, their energy levels in the SLS mini-gap will have little effect on device performance, even if the defect states lie in mid-gap. Together with our calculated defect energy level results, we can identify promising SLS designs for high-performing photodetectors.