In order to achieve the highest power plant efficiency, original equipment manufacturers continuously increase turbine working parameters (steam temperatures and pressures), improve components design, and modify start-up cycles to reduce time while providing more frequent start-up events. All these actions result in much higher levels of thermostresses, a lifetime consumption of primary components and an increased demand for accurate thermostructural and low cycle fatigue (LCF) simulations. In this study, some aspects of methodological improvement are analyzed and proposed in the frame of an integrated approach for steam turbine components thermostructural analysis, reliability, and lifetime prediction. The full scope of the engineering tasks includes aero/thermodynamic flow path and secondary flows analysis to determine thermal boundary conditions (BCs), detailed thermal/structural two-dimensional and three-dimensional (3D) finite element (FE) models preparation, components thermal and stress–strain simulation, rotor–casing differential expansion and clearances analysis, and finally, turbine unit lifetime estimation. Special attention is paid to some of the key factors influencing the accuracy of thermal stresses prediction, specifically, the effect of “steam condensation” on thermal BC, the level of detailing for thermal zones definition, thermal contacts, and mesh quality in mechanical models. These aspects have been studied and validated against test data, obtained via a 30 MW steam turbine for combined cycle application based on actual start-up data measured from the power plant. The casing temperatures and rotor–stator differential expansion, measured during the commissioning phase of the turbine, were used for methodology validation. Finally, the evaluation of the steam turbine HPIP rotor lifetime by means of a LCF approach is performed.