Rapid information processing in the human brain is vital to survival in a highly dynamic environment. The key tool humans use to exchange information is spoken language, but the exact speed of the neuronal mechanisms underpinning speech comprehension is still unknown. Here we investigate the time course of neuro-lexical processing by analyzing neuromagnetic brain activity elicited in response to psycholinguistically and acoustically matched groups of words and pseudowords. We show an ultra-early dissociation in cortical activation elicited by these stimulus types, emerging ∼50 ms after acoustic information required for word identification first becomes available. This dissociation is the earliest brain signature of lexical processing of words so far reported, and may help explain the evolutionary advantage of human spoken language.