A method and system for an enhanced uplink (EU) operation in a wireless communication system during soft handover. The system comprises a wireless transmit/receive unit (WTRU), at least two Node-Bs, and a radio network controller (RNC). One Node-B may be designated as a primary Node-B, and the primary Node-B may control EU operation during soft handover including uplink scheduling and hybrid automatic repeat request (H-ARQ). Soft buffer corruption is avoided during soft handover by controlling H-ARQ by the primary Node-B. Alternatively, an RNC may control EU operation during soft handover including H-ARQ. In this case, an RNC generates final acknowledge/non-acknowledge (ACK/NACK) decision based on the error check results of the Node-Bs.