Isernia La Pineta (south-central Italy, Molise) is one of the most important archaeological localities of the Middle Pleistocene in Western Europe. It is an extensive open-air site with abundant lithic industry and faunal remains distributed across four stratified archaeosurfaces that have been found in two sectors of the excavation (3c, 3a, 3s10 in sect. I; 3a in sect. II). The prehistoric attendance was close to a wet environment, with a series of small waterfalls and lakes associated to calcareous tufa deposits. An isolated human deciduous incisor (labelled IS42) was discovered in 2014 within the archaeological level 3 coll (overlying layer 3a) that, according to new ⁴⁰Ar/³⁹Ar measurements, is dated to about 583–561 ka, i.e. to the end of marine isotope stage (MIS) 15. Thus, the tooth is currently the oldest human fossil specimen in Italy; it is an important addition to the scanty European fossil record of the Middle Pleistocene, being associated with a lithic assemblage of local raw materials (flint and limestone) characterized by the absence of handaxes and reduction strategies primarily aimed at the production of small/medium-sized flakes. The faunal assemblage is dominated by ungulates often bearing cut marks. Combining chronology with the archaeological evidence, Isernia La Pineta exhibits a delay in the appearance of handaxes with respect to other European Palaeolithic sites of the Middle Pleistocene. Interestingly, this observation matches the persistence of archaic morphological features shown by the human calvarium from the Middle Pleistocene site of Ceprano, not far from Isernia (south-central Italy, Latium). In this perspective, our analysis is aimed to evaluate morphological features occurring in IS42.