Objective: Both, Toll-like receptor 4 (TLR4) and adiponectin signalling have been shown to reduce cardiac hypertrophy. The purpose of this study was to test the hypothesis that the TLR4 pathway interacts with adiponectin signalling during the development of cardiac hypertrophy. Methods: In mice of both genders with (C3H/HeN, WT) and without (C3H/HeJ, TLR4-D) TLR4 signalling cardiac hypertrophy was induced by transverse aortic constriction (TAC). 2 and 14 days after surgery hemodynamics were recorded. Anatomical data like left ventricular cardiac weight / tibia length (LVW/TL) and lung weight / tibia length (LW/TL) were quantified. Cardiac mRNA of adiponectin, adiponectin receptor 1 + 2, CD14, and HMGB1 was detected by qRT-PCR. Adiponectin protein serum levels were measured by ELISA. Results: 2 days after TAC the hearts did not exhibit significant hypertrophy in any of the groups, although the systolic arterial and ventricular pressure were elevated. However, after 14 days LVW/TL was significantly increased in all groups by TAC, but in TLR4-D hearts of both genders the hypertrophy was less pronounced. This pattern was also resembled by LW/TL after 14 days. Adiponectin serum levels were significantly elevated in female vs. male mice in both strains at both time points, being highest in females with aortic constriction 2 days after TAC. However, at the same time cardiac mRNA expression of adiponectin is significantly elevated in TLR4-D vs. WT animals of both genders. After 14 days of TAC differences in cardiac adiponectin mRNA expression could not be detected any longer. In contrast, HMGB1 and CD14 mRNA expression is elevated exclusively in WT mice 2 days after TAC. Conclusion: Low inflammation, indicated by low HMGB1, and high local expression of the antihypertrophic hormone adiponectin in the heart may contribute to the reduced cardiac hypertrophy in TLR4-D mice. However, serum adiponectin concentration does not seem to interact with cardiac hypertrophy.