The target reliability index is pivotal to the design, assessment, inspection, and maintenance of structures. It is commonly determined by cost optimization. However, depending on the method of quantifying fatality cost, cost optimization may lead to inconsistent target reliability indices, causing inadequate or unnecessary investment for safety improvement. A new approach to determine the target reliability index is proposed by considering cost efficiency and human safety separately. In this approach, an optimal reliability index is determined through cost optimization, circumventing the quantification of fatality cost in failure consequences. The human safety requirement is fulfilled by adding a constraint to the cost optimization problem based on different acceptance criteria for fatality risk, including individual risk criteria, societal risk criteria, and marginal lifesaving cost principle. The reliability index associated with this constraint is termed herein as an acceptable reliability index. The target reliability index is determined as the maximum between the optimal and acceptable reliability indices. A parametric study is conducted to investigate the effects of various factors on the target reliability index, including the probability density distributions and uncertainties of structural demand as well as the number of potential fatalities.