Introduction The UPR (unfolded protein response) is a cell signaling pathway which responds to accumulation of misfolded proteins in the ER (endoplasmic reticulum), called ER stress. Although the protective effects of selenium during oxidative stress in the heart are reported, it is unknown which selenoproteins mediate this protection or whether selenium protects the heart during ER stress. Recently, the UPR has also been shown to induce antioxidant proteins, including some selenoproteins. However, it is not known if these selenoproteins protect cardiac myocytes from ER stress or how the UPR induces them. Hypothesis VIMP contributes to selenium-mediated protection from oxidative stress, in cardiac myocytes. The ATF6 branch of the UPR induces Txnrd1 during ER stress. Methods Neonatal rat ventricular myocytes (NRVMs) were used to examine the importance of selenium during hydrogen peroxide (H2O2)[oxidative stress], TM (tunicamycin) [ER stress] and sI/R (simulated ischemia/reperfusion) [ER and oxidative stress]. Quantitative PCR and immunoblots were used to measure VIMP levels. VIMP was knocked down with siRNA. UPR-dependent induction of Txnrd1 was assessed with siRNA- mediated knockdown and pharmacological inhibition of ATF6, IRE1 and PERK. Also, ectopic expression of ATF6 was achieved with adenovirus (Adv). Results Selenium protects cardiac myocytes from H2O2, sI/R, and TM. TM induces three selenoproteins: Vimp, Selenok and Txnrd1. VIMP knockdown does not reduce selenium-mediated protection during H2O2, but does so during TM. Adv-ATF6 was not able to induce Txnrd1. During shorter durations of ER stress, knockdown or inhibition of ATF6 was shown to potentiate TM-mediated induction of Txnrd1. The effect was correlated with increasing levels of IRE1 mRNA. During longer durations of ER stress, PERK knockdown reduced ER stress-mediated induction of Txnrd1. Conclusion The roles of selenoproteins in protecting the heart from ER stress have not been studied in detail. Here, we report that selenium protects NRVM from oxidative and ER stresses, but VIMP only facilitates protection during ER stress. The protective effects of Vimp during ER stress are likely due to ER-associated degradation. ER stress-mediated induction of Txnrd1 was shown to depend upon IRE1 and PERK, in a time-dependent manner.