Mouse embryonic stem (ES) cells remain pluripotent in vitro when grown in the presence of leukemia inhibitory factor (LIF). LIF withdrawal results in progressive ES cell differentiation. Here we show that during this differentiation process, part of the cells undergo apoptosis concomitant with an activation of the p38 MAP kinase. To gain insight into events mediated by LIF in ES cells, the expression of potential candidate genes was analyzed in the absence or presence of this cytokine by using a semiquantitative RT‐PCR assay. We focused on early response genes and on a new type of cytokine repressors (the Socs proteins), some of which exhibit anti‐apoptotic properties. We found that expression of c‐Fos, c‐Jun, and JunB was induced upon LIF treatment whereas that of JunD, the tyrosine phosphatase ESP, and the components of the LIF receptor remained unaffected. Expression of Socs‐3, but not Socs‐1 or Socs‐2, was stimulated in the presence of LIF. Finally, uncontrolled overexpression of Socs‐1 and Socs‐3 led to repression of LIF‐dependent transcription and severely reduced cell viability, suggesting that the disturbance of a well balanced Socs protein content has adverse effects on cell survival.–Duval, D., Reinhardt, B., Kedinger, C., Boeuf, H. Role of suppressors of cytokine signaling (Socs) in leukemia inhibitory factor (LIF) ‐dependent embryonic stem cell survival. FASEB J. 14, 1577–1584 (2000)