Abstract: AIM To explore the possible mechanism of lycopene in alleviating endoplasmic reticulum stress (ERS) induced by hypoxia/reoxygenation (H/R) in H9C2 cardiomyocytes. METHODS H9C2 cardiomyocytes were randomly divided into control group, lycopene group, H/R group, lycopene+H/R group, 4-phenyl butyric acid (4-PBA)+H/R group, thapsigargin (TG) group, and lycopene+TG group. The apoptosis ratio of H9C2 cardiomyocytes was detected and the expressions of protein of glucose-regulated proteins 78 (GRP78), C/EBP homologous protein (CHOP), c-Jun-N-terminal protein kinase (JNK), phosphorylation of JNK (p-JNK) and caspase-12 were detected by Western blot. RESULTS The apoptosis ratio and the expressions of protein of GRP78, CHOP, JNK, p-JNK and caspase-12 increased markedly in H/R group and TG group in comparison with those in the control group (P<0.01). They decreased markedly in lycopene+H/R group and 4-PBA+H/R group compared with those in H/R group (P<0.01) and in lycopene+TG group compared with those in TG group (P<0.01). No statistically significant difference was found between lycopene+H/R group and 4-PBA+H/R group. No significant difference was found in the changes of the expression of protein of JNK. CONCLUSION Lycopene may exert its protective effect on H/R H9C2 cardiomyocytes through inhibiting the key signaling pathways of CHOP, p-JNK and caspase-12 to reduce ERS.