Quantum spin Hall insulators (QSHIs), also known as two-dimensional topological insulators, have emerged as an unconventional class of quantum states with insulating bulk and conducting edges originating from nontrivial inverted band structures, and have been proposed as a platform for exploring spintronics applications and exotic quasiparticles related to the spin-helical edge modes. Despite theoretical proposals for various materials, however, experimental demonstrations of QSHIs have so far been limited to two systems-HgTe/CdTe and InAs/GaSb-both of which are lattice-matched semiconductor heterostructures. Here we report transport measurements in yet another realization of a band-inverted heterostructure as a QSHI candidate-InAs/In x Ga 1-x Sb with lattice mismatch. We show that the compressive strain in the In x Ga 1-x Sb layer enhances the band overlap and energy gap. Consequently, high bulk resistivity, two orders of magnitude higher than for InAs/GaSb, is obtained deep in the band-inverted regime. The strain also enhances bulk Rashba spin-orbit splitting, leading to an unusual situation where the Fermi level crosses only one spin branch for electronlike and holelike bands over a wide density range. These properties make this system a promising platform for robust QSHIs with unique spin properties and demonstrate strain to be an important ingredient for tuning spin-orbit interaction. † These authors contributed equally to this work.