Serum concentrations of protease inhibitors (PIs) show large interindividual variations. It is not clear what clinical impact these differences in drug concentrations might have. In this study we explored the association between serum concentration of protease inhibitors and HIV-related disease. 130 patients on PI-containing regimen underwent PI concentration measurement in serum. The results were divided into 3 categories: high level, therapeutic level, and low level. HIV-related events (CDC category B and C) and death were prospectively recorded after the drug monitoring. The results were statistically analysed employing Cox regression. Median follow-up was 709 d, and 22 patients reached an endpoint. For the trough concentrations the hazard ratio (HR) for patients with therapeutic level vs low level was 0.63 (95% CI 0.20-1.95) and high level vs low level was 0.56 (95% CI 0.14-2.26). For the maximum concentrations the HR for therapeutic level vs low level was 1.32 (95% CI 0.48-3.62) and high level vs low level was 0.47 (95% CI 0.06-3.90). In conclusion, in this small pilot study we could not show any association between the serum concentrations of PIs and subsequent clinical HIV-related events. Larger studies are needed to explore this subject further.