Abstract: AIM To elucidate a possible relationship between TXNIP levels and increased activation of autophagosomes during myocardial ischemia/reperfusion (MI/R) injury. METHODS Using a MI/R mice model in TXNIP knockout and overexpressed mice, the present investigation observed whether TXNIP levels are linked to autophagy levels and MI/R injury. RESULTS Compared to Sham mice, the level of TXNIP increased during MI/R (P<0.01). After MI/R, echocardiography confirmed that TXNIP overexpression aggravated MI/R-induced cardiac dysfunction by lower LVEF% (P<0.05) and Evansblue/TTC staining revealed that TXNIP overexpression aggravated myocardium infarct size (P<0.05). In comparison, TXNIP knockout mice showed reduced MI/R-induced cardiac dysfunction by LVEF% (P<0.05) and infarct size (P<0.05) compared with wild-type (WT) mice. Further, the present investigation found that elevated TXNIP enhanced MI/R-induced autophagy activation, demonstrated by increased LC3 Ⅱ/I ratio and increased MI/R-induced autophagosome number. CONCLUSION Elevated TXNIP during MI/R aggravates MI/R-induced cardiac dysfunction, enlarges infarct size, and increases autophagy levels.