OBJECTIVES:   The aim of this study is to evaluate general practitioners’ prescription (GPs) of different Proton Pump Inhibitors (PPIs) in the period between 2005 to 2008. METHODS:   Analysis has been performed on a database of 99 medical practitioners that have managed an average of 150.000 inhabitants. We evaluate the PPIs prescriptions from January 2005 to December 2008. Evaluations performed are the following: 1) PPI prescription (total and separately for lansoprazole, esomeprazole, pantoprazole, rabeprazole, and omeprazole); 2) prevalence of the reimbursement purpose (Gastroprotection – G; Acid-Related Disease – ARD); 3) prevalence of patients with ARD categorized on the basis of PPI prescriptions as drugs box/year (1-3 short treatment – ST; 4-11 long treatment – LT; >12 very long treatment – VLT). Data were expressed as Compound Annual Growth Rate (CAGR). RESULTS:   The total volume of PPI’s prescribing increased progressively over the 4 years (CAGR +15%). The growth for each molecule was: L +42%; E +11%; P +16; R +3%; O 1%. The reimbursement purpose was significantly higher for G (CAGR +41%) than for ARD (CAGR +6%; p<0.01). We found an increase of ARD patients with VLT with a significant highest CAGR (ST +3.9%, LT +4.8%, VLT +7.4%; p<0.01). PPI prescription showed a highest CAGR for L in all patients (27%), while the lowest one was for O in VLT patients (-9%). CONCLUSIONS: Generic PPIs has unexpectedly increased the prescription of whole drug class during the period 2005-2008. We observed a marked increase in a very long duration PPI treatment for ARD  that caused a relevant resource consumption. Our data suggest that the appropriateness of PPI prescription after generic PPI introduction should be carefully monitored to distinguish between cost-effective from cost-ineffective PPI treatment.