Theophylline levels in stimulated and unstimulated mixed saliva were compared with total and free (unbound) serum theophylline levels in 11 outpatients with cystic fibrosis (CF) who were using theophylline regularly. Stimulated saliva from CF patients predicted both total and unbound serum theophylline concentrations to within ±1 μg/ml in 53.3 and 80.0%, respectively, of the samples examined. In addition, the total serum levels from CF patients could be used to predict unbound serum concentrations to within ± 1 μg/ml in 100% of the cases examined. Furthermore, it was observed that prediction equations derived in a previous study with asthmatics employing identical methodology would allow both unbound and total serum theophylline levels to be predicted from saliva levels in CF patients with a degree of accuracy and precision that was approximately equal to or slightly better than the results obtained using prediction equations derived in other CF patients. These results indicate that saliva levels allow predictions of the unbound serum theophylline levels with greater accuracy and precision than they predict total serum theophylline levels. In addition, total serum levels can be used to reliably predict unbound serum levels. The use of mixed stimulated saliva is recommended as a reliable noninvasive method for monitoring unbound serum theophylline levels. The therapeutic range for saliva, which corresponds to the accepted total serum concentration range of 10–20 μg/ml, is ∼5.55–11.3 μg/ml.