Factors affecting the plasma concentrations of the R- and S-enantiomers of fluoxetine and norfluoxetine were investigated in 131 adult patients receiving long-term fluoxetine, of 10 to 60 mg/d (mean, 24 ± 10 mg/d). Plasma concentration values (geometric means, CI 95%) in these patients were 186 (156, 223) nmol/L for S-fluoxetine, 67 (58, 77) nmol/L for R-fluoxetine, 247 (212, 287) nmol/L for S-norfluoxetine, and 118 (102, 137) nmol/L for R-norfluoxetine. The difference between the concentrations of the respective R- and S-enantiomers was statistically significant (P < 0.0001) for both the parent drug and the demethylated metabolite. A significant correlation was found between the concentrations of each enantiomer and the prescribed daily dosage (r = 0.44, P < 0.0001 for S-fluoxetine; r = 0.48, P < 0.0001 for R-fluoxetine; r = 0.36, P < 0.0001 for S-norfluoxetine; r = 0.32, P = 0.0003 for R-norfluoxetine), but the variability in concentration at any given dosage was considerable. When an iterative model based on multiple polynomial regressions was applied to determine the potential contributions of dosage, age, gender, body weight, and concomitant medication to the variability in the plasma concentration of the enantiomers, dosage was consistently found to provide the greatest predictive value. The predictive value of the model could be consistently improved when concentrations of other enantiomers were included as covariates. Of 58 patients with depressive symptoms for whom evaluation of clinical response (CGI scale) was available, 33 (57%) responded favorably to treatment. The plasma levels of individual enantiomers and of the active moiety (ActM, sum of the concentrations of R-fluoxetine, S-fluoxetine, and S-norfluoxetine) in these patients did not differ significantly from those found in patients with unsatisfactory therapeutic response. Likewise, the concentrations of individual enantiomers and of the ActM were similar in patients with or without adverse effects. Overall, these results demonstrate that the pharmacokinetics of fluoxetine and norfluoxetine exhibit marked stereoselectivity and considerable interpatient variability, which could not be explained by differences in gender, age, or comedication. In addition, a considerable variability was found in the enantiomers' concentrations associated with a favorable therapeutic response.