Both hypoxic and inflammatory conditions activate transcription factors such as hypoxia-inducible factor (HIF)-1 alpha and nuclear factor (NF)-kappa B, which play a crucial role in adaptive responses to these challenges. In dendritic cells (DC), lipopolysaccharide (LPS)-induced HIF1 alpha accumulation requires NF-kappa B signaling and promotes inflammatory DC function. The mechanisms that drive LPS-induced HIF1 alpha accumulation under normoxia are unclear. Here, we demonstrate that LPS inhibits prolyl hydroxylase domain enzyme (PHD) activity and thereby blocks HIF1 alpha degradation. Of note, LPS-induced PHD inhibition was neither due to cosubstrate depletion (oxygen or alpha-ketoglutarate) nor due to increased levels of reactive oxygen species, fumarate, and succinate. Instead, LPS inhibited PHD activity through NF-kappa B-mediated induction of the iron storage protein ferritin and subsequent decrease of intracellular available iron, a critical cofactor of PHD. Thus, hypoxia and LPS both induce HIF1 alpha accumulation via PHD inhibition but deploy distinct molecular mechanisms (lack of cosubstrate oxygen versus deprivation of co-factor iron).