Based on the basic principle of spread spectrum systems, this paper proposes a hybrid automatic-repeat-request (HARQ) scheme with interference mitigation for multiple-input-multiple-output (MIMO) orthogonal frequency-division multiplexing (OFDM) systems. The proposed hybrid media access control (MAC) and physical layer (PHY) design orthogonally spreads signals in the transmission domain to separate the desired signals from interferences. It not only improves the signal-to-noise ratio (SNR) but also suppresses intercarrier interference (ICI) and interantenna interference (IAI). Almost without increasing complexity, mathematical analyses and numerical simulations show that the proposed scheme outperforms the conventional Chase combining HARQ.