<p>This study proposes a non-probabilistic reliability-based topology optimization (NRBTO) method based on isogeometric analysis (IGA), considering the structural stiffness performance. In this study, a geometric model was constructed using non-uniform rational B-splines (NURBS), and the NURBS basis function was used as the shape function of the analytical model. In topology optimization, the classic finite element method (FEM) was replaced by a mesh-independent IGA method. The formulation of isogeometric topology optimization (ITO) based on the solid isotropic microstructures with penalization (SIMP) interpolation model was derived, and a sensitivity analysis was performed using the adjoint method. Considering the uncertainties of material properties and loads, the parameter uncertainty is quantified by interval theory, the propagation analysis is conducted using the interval parametric vertex method, the optimization feature distance is selected as the non-probabilistic reliability-based index, and a sensitivity analysis is performed on the reliability index to establish a reliability-based topology optimization method based on isogeometric analysis. The method of moving asymptotes (MMA) is used to solve the optimization problem. Several numerical examples were used to verify the method’s effectiveness in practical applications.</p>