This paper presents a clonal selection operation: clonal selection operation based on orthogonal experiment design (CSO-OED). This design is later combined with the typical clonal selection operation and results in two algorithms: CSO+CSO-OED(I) adopting parallel mechanism and CSO+ CSO-OED(II) adopting series mechanism. The validation in 9 classical benchmark functions and 6 complex functions has showed that CSO-OED can not only maintain the diversity of population, but also help avoid premature. Implemented in CSO+CSO-OED(I) and CSO+CSO-OED(II), the strategy that separates the local search and global search can not only guarantee the convergence but also improve the accuracy of global solution and the robustness of the algorithm.