Apoptosis, or programmed cell death, is vital for multicellular organisms, particularly during developmental processes but also throughout their entire lives, and must therefore be carefully balanced. Recently, it has been shown that Hydra epithelial cells show a graded sensitivity to apoptosis depending on their position along the body axis, significantly higher in the apical region than along the gastric column. Using RNA-seq analysis, one gene, HyBcl-2-l8, caught our attention as it is expressed only in epithelial cells and shows a graded expression with a higher level in the Hydra head than in the body column, thus mimicking the gradient of cell death sensitivity in epithelial cells. This gene is a member of the Bcl-2 family, involved in maintenance of the outer mitochondrial membrane integrity. These proteins prevent the leakage of certain components that are responsible for triggering molecular pathways that undoubtedly lead to programmed death of the cell. HyBcl-2-l8 is present in two isoforms in Hydra and is expressed in the gastrodermal epithelial lineage. Recent data have shown that when overexpressed in human cells and upon apoptosis induction, HyBcl-2-l8 has a pro-apoptotic effect. However, only a few studies have investigated the role of Bcl-2 family members in Hydra in vivo. The first method to interrogate the function of this gene was to silence it by delivering a hairpin carried by a vector plasmid. Under these conditions, HyBcl-2-l8 showed no pro-apoptotic effect. The second method used to study the function of HyBcl-2-l8 was by delivering siRNAs through electroporation. On Hv_Basel, the different assays showed a significant decrease in apoptosis after cell death induction and TUNEL assay. Furthermore, differences in the length of the animals were observed. Therefore, this suggests a pro-apoptotic effect of HyBcl-2-l8 in Hydra in vivo. The same experiments were repeated on Hv_AEP, this time no significant decrease in gene expression level was detected, nor any reduction in cell death after induction by wortmannin. Finally, the experiments were redone on Hv_AEP after treatment with hydroxyurea (HU), thereby suppressing most interstitial cells. Under these conditions, a small reduction in the gene expression level was detected and was correlated with a significant decrease in apoptosis in the body column after cell death induction. These results, allow us to assume a pro-apoptotic role of HyBcl-2-l8 in both distinct strains of Hydra, the intact Hv_Basel and in the Hv_AEP deprived of their interstitial cells but not in the intact Hv_AEP, probably due to the low gene silencing level obtained under the experimental conditions used in this study.