This work reports on a study into the design of creep-resistant precipitation-hardened austenitic steels using an integrated thermodynamics-based model in combination with a genetic algorithm optimization routine. The key optimization parameter is the secondary stage creep strain at the intended service temperature and time, taking into account the coarsening rate of MX carbonitrides and its effect on the threshold stress for secondary creep. The creep stress to reach a maximal allowed creep strain (taken as 1%) at a given combination of service temperature and time is formulated and maximized. The model was found to predict the behaviour of commercial austenitic creep-resistant steels accurately. By means of the alloy optimization scheme, three new steel compositions are presented, yielding optimal creep strength for various intended service times (10, 103, 105 h). According to the evaluation parameter employed, the newly defined compositions will outperform existing precipitate-strengthened austenitic creep-resistant steels.