Salusin-α and salusin-β are newly identified bioactive peptides with hemodynamic and mitogenic activities. Recent studies have shown that salusins improve calcium uptake and protein synthesis in neonatal rat cardiomyocytes, suggesting that salusins may be regulatory factors for myocardial growth and hypertrophy. In this study, we investigated whether salusins improve the survival of cardiomyocytes after serum deprivation. Cultured neonatal cardiomyocytes were treated with or without salusins (salusin-α or salusin-β) at a concentration range of 10−10 to 10−8 mol/L for 24 h under serum deprivation conditions. Cardiomyocytes viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazonium bromide assay. Cell death or apoptosis rate was identified by flow cytometry analysis. Compared to serum deprivation-only groups, cardiomyocyte viability was significantly increased in salusin-α or salusin-β groups. Cell death rate was decreased after administration of 10−8 mol/L salusin-α or salusin-β. Salusin-β was able to decrease the apoptotic rate. Salusins also increased the expression of cardiomyocyte glucose-regulated protein 78 (GRP78) as estimated by Western blot. Furthermore, antisense oligodeoxynucleotide specifically against GRP78 attenuated or abrogated antiapoptosis or survival effects of salusin-β. These findings suggest that salusin-α and salusin-β may be a potential survival factor against serum deprivation-induced myocardial cell death and that this cardioprotective effect may involve an upregulation of GRP78 expression in cardiomyocytes.