Differential space-time (DST) modulation has been proposed recently for multiple-antenna systems over Rayleigh fading channels, where neither the transmitter nor the receiver knows the fading coefficients. Among existing schemes, differential modulation is always performed in the time domain and suffers performance degradations in frequency-selective fading channels. In order to combat the fast time and frequency-selective fading, a novel time-frequency differential space-time (TF-DST) modulation scheme, which adopts differential modulation in both time and frequency domains, is proposed for multi-antenna orthogonal frequency division multiplexing (OFDM) system. A corresponding sub-optimal yet low-complexity non-coherent detection approach is also proposed. Simulation results demonstrate that the proposed system is robust for time and frequency-selective Rayleigh fading channels. Differential space-time (DST) modulation has been proposed recently for multiple-antenna systems over Rayleigh fading channels. Where existing the transmitter, the differential modulation is always performed in the time domain and suffers performance degradations in frequency-selective fading channels. In order to combat the fast time and frequency-selective fading, a novel time-frequency differential space-time (TF-DST) modulation scheme, which holds differential modulation in both time and frequency domains, is proposed for multi-antenna orthogonal frequency division multiplexing (OFDM) system. A corresponding sub-optimal yet low-complexity non-coherent detection approach is also proposed. Simulation results demonstrate that the proposed system is robust for time and frequency-selective Rayleigh fading channels .