BACKGROUND: Plasma citrulline is a biomarker of enterocyte mass and function in humans. OBJECTIVE: We evaluated citrulline in the reemerging context of diarrhea in HIV-infected patients receiving highly active antiretroviral therapy. DESIGN: This study prospectively measured citrulline in 6 groups of HIV-1 patients (n = 115): 1) undetectable viral load without chronic diarrhea (a; n = 40) and with protease inhibitor-associated toxic chronic diarrhea (b; n = 26), 2) detectable viral load and CD4 > 200/mm(3) without (a; n = 6) and with (b; n = 11) chronic diarrhea, and 3) detectable viral load and CD4 <200/mm(3) without chronic diarrhea (a; n = 7) and with opportunistic intestinal infections or HIV enteropathy (b; n = 25). The influence of diarrhea on citrulline was assessed by comparing the a and b subgroups with healthy control subjects (n = 100). RESULTS: Citrulline was slightly decreased (22-30 micromol/L) in groups 1b and 2b and was <22 micromol/L in 19 of 25 patients in group 3b. In group 3b, a citrulline concentration <10 micromol/L was associated with a clinical indication for parenteral nutrition (n = 6 of 8 compared with 2 of 17 if the citrulline concentration was >10 micromol/L; P < 0.05). Citrulline correlated positively with albumin (P < 0.01) and BMI (P < 0.05) and negatively with C-reactive protein (P < 0.01). When antiinfectious and nutritional therapies were successful (n = 18 of 25), citrulline normalized in 2-12 wk. Neither chronic hepatic or pancreatic disease nor lipodystrophy and the metabolic syndrome affected citrulline. Compared with control subjects (38 +/- 8 micromol/L), patients without chronic diarrhea (groups 1a, 2a, and 3a) had normal citrulline concentrations (36 +/- 6 micromol/L). CONCLUSIONS: Plasma citrulline is a reliable biomarker of enterocyte functional mass in HIV patients. Citrulline does not allow the etiologic diagnosis of enteropathy, but it can discriminate between protease inhibitor toxic diarrhea and infectious enteropathy and quantify the functional consequences, which makes it an objective tool for indicating the need for parenteral nutrition.