Context From one country to another, the pay-for-performance mechanisms differ on one significant point: the identification of target populations, that is, populations which serve as a basis for calculating the indicators. The aim of this study was to compare clinical versus medication-based identification of populations of patients with diabetes and hypertension over the age of 50 (for men) or 60 (for women), and any consequences this may have on the calculation of P4P indicators. Methods A comparative, retrospective, observational study was carried out with clinical and prescription data from a panel of general practitioners (GPs), the Observatory of General Medicine (OMG) for the year 2007. Two indicators regarding the prescription for statins and aspirin in these populations were calculated. Results We analyzed data from 21.690 patients collected by 61 GPs via electronic medical files. Following the clinical-based approach, 2.278 patients were diabetic, 8,271 had hypertension and 1.539 had both against respectively 1.730, 8.511 and 1.304 following the medication-based approach (% agreement = 96%, kappa = 0.69). The main reasons for these differences were: forgetting to code the morbidities in the clinical approach, not taking into account the population of patients who were given life style and diet rules only or taking into account patients for whom morbidities other than hypertension could justify the use of antihypertensive drugs in the medication-based approach. The mean (confidence interval) per doctor was 33.7% (31.5–35.9) for statin indicator and 38.4% (35.4–41.4) for aspirin indicator when the target populations were identified on the basis of clinical criteria whereas they were 37.9% (36.3–39.4) and 43.8% (41.4–46.3) on the basis of treatment criteria. Conclusion The two approaches yield very “similar” scores but these scores cover different realities and offer food for thought on the possible usage of these indicators in the framework of P4P programmes.