OBJECTIVES: Pharmacoeconomic analyses present the basis for the evaluation of the therapy rationalization within a certain population. Antibiotics are among the most often prescribed medications in primary health care. In total expenditure, antibiotics amount to 16, 15% of the total healthcare budget on the territory of Nis. The aim of our work was to monitor and analyze the out-patient usage of antibiotics in Nis area, in the period of 2003 to 2005. METHODS: By using the ATC/DDD methodology, we analyzed the expenditure of the antibiotics and presented the results as the defined daily doses(DDD) for 1000 citizens per day. RESULTS: The total usage of antibiotics increased in 2005 (22.83:25.96 DDD/1000/a day, p<0.05). The most frequently prescribed antibiotics are half-synthetic penicillins(9.67:10,0 DDD/1000/a day), then follow macrolides with a significant tendency of growth (3.05:4.9 DDD/1000/a day, p<0.05). The biggest growth has been registered with the usage of azitromycin (0.26:0.7 DDD/1000/day), the number of prescribed recipes shows the growth of 164%. The usage of antibiotics shows the growth of 14% in the year 2005 regarding 2003. By analyzing the number of prescribed recipes, the growth of 3, 2% in the prescribing of the antibiotics has been registered. It is important to point out that all prescribed antibiotics were on the positive drug list. CONCLUSIONS: This analyzes showed an irrational usage of the antibiotics in primary health care in Nis area, which requires additional application of educative programs. The cited results will be basis for further evaluations of the rationality in the usage of antibiotics in primary health care.