Multiple-Input Multiple-Output (MIMO) signal processing combined with Orthogonal Frequency Division Multiplexing (OFDM) is a widely accepted solution to achieve the high bit rates that new communication standards require in frequency-selective wireless channels. In recent years, a new Frequency-Domain Equalized (FDE) Cyclic-Prefixed Single-Carrier (CPSC) block transmission system has been proven to achieve similar performance to OFDM for coded systems with the same overall complexity, avoiding its main drawbacks and becoming a candidate for future wireless standards. In this paper, a FDE CPSC spatial multiplexing system is analyzed and compared to OFDM. The applicability of different frequency-domain MIMO equalization and detection schemes is evaluated. Simulation-based performance results prove the potential of these techniques and highlight that FDE CPSC can equal or outperform OFDM in uncoded and high coding rate spatial multiplexing systems, as it has been shown in the literature for the SISO case.