Objective To study the cholesterol nuclear-cytoplasmic interaction effect and position cholesterol traits QTL in mice. Methods Improving the nuclear-cytoplasmic interaction models and methods that have been constructed, and analyzing the public database of total cholesterol and lipoprotein data of F2 group that derived from DBA/2J (D2) and CAST/EiJ (CAST) mice. Results Six QTL that controlling total cholesterol, HDL and nonHDL were located in 4 linkage groups in the genome. In the models constructed in this study, we found a QTL has significant interaction with cytoplasmic background, which changes the previous results of data analysis, the genetic mouse cholesterol and lipoprotein components opened up new ideas. Conclusion Mouse cholesterol trait is the result of interaction of nuclear genes and cytoplasmic background.