Partly laminated sediments were sampled from the brine-filled, anoxic Shaban Deep basin in the northern Red Sea. At about 4200 cal yr BP more than two millennia of anoxic sedimentation is replaced by a sub-oxic facies strongly suggesting the episodic absence of the brine. At the same time stable oxygen isotopes from surface dwelling foraminifera show a sharp increase (within less than 100 yr) pointing to a strong positive salinity anomaly at the sea surface. This major evaporation event significantly enhanced the renewal of deep water and the subsequent ventilation of the small Shaban Deep basin. The timing and strength of the reconstructed environmental changes around 4200 cal yr BP suggest that this event is the regional expression of a major drought event, which is widely observed in the neighboring regions, and which strongly affected Middle East agricultural civilizations.