The present work was carried out to evaluate the effect of two salting technologies [dry salting (DS) and the combined dry-brine salting (DBS)] on the chemico-physical and microbiological characteristics of PDO Pecorino Siciliano cheeses of different final weight (6 and 12 kg). Dry matter was significantly influenced by both salting process and final size. Twelve kilogram cheeses treated by DBS showed higher protein content with higher soluble nitrogen per cent than 6 kg cheeses. Salt content was in the range 3.1–4.0% on dry matter. The colour did not show significant differences for any of the factors, but 12 kg cheeses subjected to DS showed higher yellow index than the other cheeses. The resistance at 30% of strain was influenced by cheese size, with 6 kg cheeses showing higher resistances than 12 kg cheeses. All cheeses were dominated by coccus LAB, but pseudomonads and Enterobacteriaceae showed comparable levels of about 105 cfu/g. Significant microbiological differences were evidenced only for enterococci and yeasts concerning the final cheese size. Thirteen species of LAB, belonging to five genera (Enterococcus, Lactobacillus, Lactococcus, Pediococcus and Streptococcus), were identified, but several spoilage/pathogenic species were also identified, especially Pseudomonas putida, Citrobacter freundii and Stenotrophomonas maltophilia. LAB isolates were preliminary evaluated for their physiological characteristics in view of developing autochthonous starters to improve the microbiological quality of PDO Pecorino Siciliano cheese.