A sampling optimization method based on color difference analysis was proposed in this paper. Firstly, three color sets--respectively a super set used to simulate the whole CMYK color space, a test set for characterization accuracy verification and an initial characterization set were defined and created. Secondly, the colorimetric values of test set can be predicted according to the characterization results of the current characterization set. Thirdly, by analyzing the color difference of test set, 10% samples with larger color difference were selected as the larger color difference set to carry on optimization. After that, the samples in the super set which are closest to the larger color difference set were found and added to the characterization set. Finally, cyclic optimization was conducted until the characterization accuracy meets the given requirements. Experimental results showed a significant reduction in the number of samples with an improvement of characterization accuracy.