Layout dependence of total-ionizing-dose (TID) response, hot-carrier degradation (HCD), and radiation-enhanced HCD (REHCD) in 65-nm bulk Si nMOSFETs are experimentally investigated in this article. For TID response, the average irradiation-induced Vth shift slightly increases by several millivolts with increasing gateto-active area spacing (SA), which is contrary to the trend previously observed in pMOSFETs. HCD is much more severe in irradiated devices and the average hot-carrier-stress-induced Vth shift continuously decrease with increasing SA for both irradiated and unirradiated devices, indicating potential better hot-carrier reliability with larger SA. Finally, layout dependence of REHCD is illustrated. REHCD is enhanced with increasing SA, which may reduce the reliability improvement of irradiated devices with larger SA. These layout dependencies are attributed to larger tensile strain in the channel. The results provide early insights into the layout dependence of TID effects and HCD, highlighting potential concerns on the reliability of devices working in radiation environment.