Tetracycline is a powerful tool for controlling the expression of specific transgenes (TG) in various tissues, including heart. In these mouse systems, TG expression is repressed/enhanced by adding doxycycline (Dox) to the diet. However, Dox has been shown to attenuate matrix metalloproteinase (MMP) expression and activity in various tissues, and MMP inactivation mitigates left ventricular (LV) remodeling in animal models of heart failure. Therefore, we examined the influence of Dox on LV remodeling and MMP expression in mice after transverse aortic constriction (TAC). One month after TAC, cardiac hypertrophy (99 vs 67%) and the proportion of mice exhibiting congestive heart failure (CHF, 74 vs 32%) were higher in the TAC+Dox group than in the TAC group (p<0.05). These differences were no longer seen two months after TAC, although LV was more severely dilated in TAC+Dox than in TAC (p<0.05). One month after TAC, the increase in BNP and -MHC mRNA levels was 1.6 and 1.7 times higher, respectively, in TAC+Dox than in TAC (p<0.01). MMP 2 gelatin zymographic activity increased 1.9- and 2.4-fold in TAC and TAC+Dox, respectively (p<0.01 and p<0.05 relative to respective Shams), but the difference between TAC+Dox and TAC did not reach statistical significance. Dox did not alter significantly TAC-associated perivascular and interstitial myocardial fibrosis. These findings demonstrate that Dox accelerates the onset of cardiac hypertrophy and progression to CHF following TAC in mice. Accordingly, care should be taken when designing and interpreting studies based on TG mouse models of LVH using the tet-on/tet-off system.