The sialomucin CD43 is highly expressed on most hematopoietic cells. In this study, we show that the CD43 ectodomain is shed from murine granulocytes, mast cells, and T cells, but not from macrophages. To study the significance of CD43 shedding, we constructed 2 CD43/34 chimeras in which the CD43 membrane-proximal or transmembrane domain was swapped with the corresponding domain from CD34 that is not shed from cells. Viability of cells that normally shed CD43 was negatively affected when forced to express either of the 2 CD43/34 chimeras, but toxicity was reduced when cells coexpressed wild-type CD43. The CD43 cytoplasmic tail (CD43ct) was found to translocate into the nucleus, and inhibition of either its nuclear translocation or its release by gamma-secretase was proapoptotic. Involvement of CD43 in regulation of apoptosis is consistent with our findings that CD43ct was modified by small ubiquitin-like modifier-1 and was colocalized with promyelocytic nuclear bodies. CD43-deficient cells exhibited reduced levels of promyelocytic nuclear bodies and had increased sensitivity to apoptosis induced by growth factor withdrawal or T-regulatory cell suppression. Taken together, our data indicate an essential function of CD43 processing and nuclear localization of CD43ct in cell homeostasis and apoptosis.