Indinavir plasma levels are associated with antiretroviral efficacy however few data is available regarding toxicity. We assessed the relationship between indinavir pharmacokinetic (PK) characteristics and severe nephrolithiasis as well as other severe or serious adverse reactions (SAR). Patients included in the ANRS CO8 APROCO-COPILOTE cohort and receiving indinavir 800 mg thrice daily as first line protease inhibitor, were eligible for this study. To be included in the analysis, their plasma sample at month 1 (M1) had to be available (n=282) to estimate, using population PK modelling, indinavir PK characteristics, i.e. maximum (C max ) and trough plasma (C res ) concentrations, area under the curve (AUC) and observed/predicted concentrations ratio (CR). A Cox model was used to estimate the independent effect of C max , C res , AUC and CR on the hazard of severe nephrolithiasis and SAR. At M1, median C max was 6 205 ng/mL, C res : 631 ng/mL, AUC: 24 242 ng.h/mL and CR: 0.6. After a median follow-up of 12 months, 11% of patients (30/282) had experienced at least one SAR among which 12 were nephrolithiasis.In the multivariate analyses, early high indinavir C res (i.e. ≥ 1000 ng/mL at M1) was associated with a higher rate of severe nephrolithiasis (HR=6.7; 95% confidence interval=1.8-25.2; p<0.01) and was also associated with a higher rate of all SAR but only when nephrolithiasis were included among those cases. Prospective and early indinavir C res determination should be recommended in the patient's care management and dosage adjustments.