Method and apparatus for uplink transmission using multiple antennas are disclosed. A wireless transmit/receive unit (WTRU) performs space time transmit diversity (STTD) encoding on an input stream of a physical channel configured for STTD. Each physical channel may be mapped to either an in-phase (I) branch or a quadrature-phase (Q) branch. The WTRU may perform the STTD encoding either in a binary domain or in a complex domain. Additionally, the WTRU may perform pre-coding on at least one physical channel including the E-DPDCH with the pre-coding weights, and transmitting the pre-coded output streams via a plurality of antennas. The pre-coding may be performed either after or before spreading operation.