Objective To established cardiac-specific transgenic mice of the cTnC^D145E and cTnC^G159D and compare the HCM and the DCM. Methods The cTnC^D145E and cTnC^G159D were generated by site-directed mutagenesis and the transgenic plasmids were constructed by insertion of the mutant genes under the control of α-MHC, which is a myocardium specific promoter. The transgenic mice were generated by microinjection and were all maintained on a C57BL/6J genetic backgroud. The cardiac structure and function of the transgenic mice were compared and analysized by echocardiographic and pathological observation at different ages. Results The cTnC^D145E and cTnC^G159D transgenic mice were established and developed to HCM and DCM, respectively, with aging. The left ventricular end-systolic volume (ESV) and left ventricular end-diastolic volume (EDV) decreased and ejection fraction (EF) and left ventricular end-systolic posterior wall thickness (ESPWT) increased in the cTnC^D145E transgenic mice, while EDV and ESV increased and EF and ESPWT decreased in the cTnC^G159D transgenic mice at 12 months of age. Conclusions Cardiac-specific human cTnC^D145E transgenic mice showed HCM phenotypes, and cardiac-specific human cTnC^G159D transgenic mice showed DCM phenotypes, which can be used as different models for comparative study of the pathogenesis of cardiomyopathy.