During the conceptual design phase of an accelerator-driven sub-critical system (ADS), the reliability requirements of safety systems need to be determined for future practical construction to balance the economy performance with the safety performance. In this paper, the design optimization of the safety-related systems reliability for the ADS based on China LEAd-based Research Reactor was performed by applying the lines of defense (LODs) method to this ADS. First, a tentative LOD type, such as a strong line (a LOD) or a medium line (b LOD), was assigned to the main safety related systems. These systems include the accelerator trip system, decay heat removal system, reactor vessel, secondary cooling system isolation, decompression system, emergency diesel engine, and containment systems. Second, the failure of the LODs were combined with initiating events that were identified early, and a preliminary list of design extension conditions (DECs) was obtained. Third, the suitability of the conditions for classification into the design basic condition (DBC) or the DEC and their unacceptable consequences for the DBC or criteria limitation were discussed. Last, the LOD types of safety systems were re-assigned considering the results to optimize the design. The complementary events in the list of DECs are obtained. This paper can provide important references for the construction and operation of future ADSs.