A clinical study was conducted to compare the use of oral fluid to urine for compliance monitoring of pain patients. Patients (n = 133) undergoing treatment for chronic pain at four clinics participated in the study and provided paired oral fluid and urine specimens. Oral fluid specimens were collected with Quantisal(TM) saliva collection devices immediately following urine collection. Oral fluid specimens were analyzed for 42 drugs and/or metabolites by validated liquid chromatography-tandem mass spectrometry procedures. Accompanying urine specimens were initially screened by immunoassay and non-negative results were confirmed. Of the 1544 paired tests, 329 (21.3%) drug analytes were positive, and 984 (63.7%) were negative for both specimens resulting in an overall agreement of 85%. There were 83 (5.4%) analyte results that were positive in oral fluid and negative in urine, and 148 (9.6%) were negative in oral fluid and positive in urine for an overall disagreement of 15%. Cohen's Kappa value was 0.64, indicating "substantial" agreement. The primary exceptions to agreement were the lower detection rates for hydromorphone, oxymorphone, and benzodiazepines in oral fluid compared to urine. The authors conclude that, overall, oral fluid tests produced comparable results to urine tests with some minor differences in detection rates for different drug classes.