Monocytes migrate to various tissues and differentiate to macrophages and mediate early control of pathogens. Various alternative pathways of cell death have been discovered which have been shown to play a key role in host survival. Herein, we investigated the impact of differentiation of monocytes to macrophages on their susceptibility to two distinct cell death inducing complexes, ripoptosome and necrosome. Our results indicate that differentiation of macrophages results in resistance to ripoptosome- but not necrosome- induced cell death. Additional experiments indicated that the resistance to ripoptosome signaling correlated with reduced caspase activation and enhanced expression of anti-apoptotic mediators XIAP and cFLIPL. Our results also reveal the contradictory roles of p38 MAPK/MK2 in stimulating (phosphorylating RipK1) or inhibiting (reducing TNF-α expression and caspase 8 activation) ripoptosome signaling. These findings reveal novel mechanistic insights that can be exploited for development of therapeutics.