Cocaine (COC) is widely abused and associated with significant adverse effects. Forensic and clinical laboratories often test for COC intake through detection of the primary metabolite, benzoylecgonine (BZE) in urine. Testing for BZE alone may result in false-negative determinations in situations where COC is recently administered or metabolism is impaired. To our knowledge, no data have been provided demonstrating the utility of adding parent COC to urine confirmation testing in routine analyses. For this study, random urine specimens from patients undergoing treatment for pain management and/or addiction were collected over six months from 800 clinics across 39 states. A total of 7,587 urine specimens tested positive for a COC marker (COC and/or BZE). A positive result was determined using a liquid chromatography-tandem mass spectrometry (LC-MS-MS) method with a limit of quantitation of 50 ng/mL. Of the positive specimens, 26% and 97% were positive for COC and BZE, respectively. Positive BZE-only specimens represented 74% of total positive specimens. However, 231 of the 7,587 urine specimens (3% of positive specimens) were positive for COC in the absence of BZE. The 231 COC-only positive specimens were collected from 206 patients, and two of these patients provided four COC-only positive specimens. Of a select group of COC-only specimens tested by both LC-MS-MS and immunoassay (IA) (N = 32), 81% were negative by IA, demonstrating the limitation of screening with BZE-specific IAs. A false-negative COC result can have profound impacts such as a delay in patient referral to addiction treatment, unintentional prescribing of a controlled substance to a patient actively abusing an illicit substance, or undetected cocaine use in the workplace. This study highlights the importance of testing for COC in addition to BZE in forensic and healthcare settings.