Archaeological investigations of the Colline Metallifere district (Southern Tuscany, Italy) have highlighted several Medieval sites located close to the main Cu-Pb-Fe (Ag) ore occurrences. This study is focused on the investigation of late-medieval slags from Cugnano and Montieri sites using both geochemical and mineralogical methods to understand slag heterogeneities as result of ore differences and technological processes. Matte-rich slags present in both sites (with abundant matte ± speiss and frequent relict phases) represent waste products related to primary sulphide ore smelting to obtain a raw lead bullion. The distribution of slags between the Ca-rich or Fe-rich dominant composition, and the consequent mineralogy, are tracers of the different ore–gangue association that occurred in the two sites. Silver is present only in very small matte-rich slags and ores enclosed within the mortar of the Montieri site; wastes derived from silver-rich mineral charges were probably crushed for the recovery of silver. Matte-poor slags found at Montieri represent a second smelting; raw lead bullion obtained from matte slags (both Fe- and Ca-rich) was probably re-smelted, adding silica and Al2O3-phase-rich fluxes, under more oxidizing conditions to reduce metal impurities. This second step was probably employed for Zn-rich lead ores; this process helped to segregate zinc within slags and improve the quality of the metal.