This study aimed to identify therapeutic approaches and the tendencies of Gram-positive infections in Spanish hospitals in terms of prevalence, origin, location and etiology, as well as the characteristics of patients with these infections, their underlying illnesses, the severity and predisposing factors. We used statistical analysis to compare the results of two multicenter prevalence studies, the first from 1994-1995, and the second in 1998. We found a statistically significant decrease in the percentage of infected patients (45.8% vs. 32.8%; p <0.001), but an increase in infections by Gram-positive microorganisms (14.4% vs. 20.6%; p <0.001), which was reflected in the increased use of glycopeptides (17.1% vs. 31.2%; p = 0.002). The use of quinolones also increased. The most common underlying illnesses were heart disease and diabetes mellitus, and there was a reduction in the number of patients infected by HIV and in users of parenteral medication. The decrease in outpatient infections indicated that nosocomial infection was more frequent in the second study, in which the number of predisposing factors increased (52.3% vs. 79.2%; p <0.001), the most common of which were peripheral line, immobilization and a bladder catheter. Bacteremia was the most frequent infection, and there was a reduction in lower respiratory tract infections and an increase in skin and soft tissue infections. Staphylococcus aureus was the most frequently found microorganism and showed a significant increase in incidence (27.2% vs. 47.9%; p <0.001), whereas pneumococcus showed a decrease (15.0% vs. 5.2%; p = 0.012). It was concluded that despite the decrease in the percentage of infected patients and severely ill patients, there is an increase in Gram-positive infections, especially bacteremia, and in the use of more aggressive treatments. This may reflect the increase in resistant isolates.