Abstract Design of structures against multiple hazards has become an important consideration for many important engineering facilities such as major structures and bridges. A central issue is proper consideration of the uncertainty in the demand and capacity and the balance of reliability against costs. In this study this problem is investigated based on minimization of expected lifecycle cost. The uncertainties in the loads and resistance are modeled by random processes and random variables. Costs of construction, consequences of structural limit states including damage, revenue loss, death and injury as well as discounting cost over time are considered. The importance of various design parameters is first examined by a parametric study. The method is then applied to design of a multistory office building against winds and earthquakes in Los Angeles, Seattle, and Charleston. The sensitivity of optimal design to important but uncertain design parameters such as structural life, discount rate and death and injury cost is investigated. The question of uniform reliability against different hazard is also examined. It is found that an optimization-based design is a viable approach to design against multiple hazards. The design is highly dependent on failure consequence and moderately sensitive to assumption of structural life span and discount rate. It may or may not be sensitive to death and injury cost assumption dependent on location and hazard risk characteristics. Uniform reliability against different hazards is not required. The design is often dominated, but not controlled, by the hazard that has large uncertainty and causes large consequences.