The Amudian (late Lower Paleolithic) site of Qesem Cave in Israel represents one of the earliest examples of habitual use of fire by middle Pleistocene hominids. The Paleolithic layers in this cave were studied using a suite of mineralogical and chemical techniques and a contextual sedimentological analysis (i.e., micromorphology). We show that the lower ca. 3m of the stratigraphic sequence are dominated by clastic sediments deposited within a closed karstic environment. The deposits were formed by small-scale, concentrated mud slurries (infiltrated terra rosa soil) and debris flows. A few intervening lenses of mostly in situ burnt remains were also identified. The main part of the upper ca. 4.5 m consists of anthropogenic sediment with only moderate amounts of clastic geogenic inputs. The deposits are strongly cemented with calcite that precipitated from dripping water. The anthropogenic component is characterized by completely combusted, mostly reworked wood ash with only rare remnants of charred material. Micromorphological and isotopic evidence indicates recrystallization of the wood ash. Large quantities of burnt bone, defined by a combination of microscopic and macroscopic criteria, and moderately heated soil lumps are closely associated with the wood-ash remains. The frequent presence of microscopic calcified rootlets indicates that the upper sequence formed in the vicinity of the former cave entrance. Burnt remains in the sediments are associated with systematic blade production and faunas that are dominated by the remains of fallow deer. Use-wear damage on blades and blade tools in conjunction with numerous cut marks on bones indicate an emphasis on butchering and prey-defleshing activities in the vicinity of fireplaces.