The New York City Department of Health and Mental Hygiene (NYC DOHMH) operates 10 sexually transmitted disease (STD) walk-in clinics offering various free services, including confidential or anonymous testing for human immunodeficiency virus (HIV). In January 2004, the STD clinics introduced on-site rapid HIV testing of finger-stick whole-blood specimens using the OraQuick(R) brand test (OraSure Technologies, Bethlehem, Pennsylvania). In March 2005, the clinics replaced finger-stick whole-blood testing with oral fluid testing with the OraQuick Advance Rapid HIV-1/2 Antibody Test. The clinics use Western blot confirmatory tests on serum to confirm all whole-blood or oral fluid reactive (i.e., preliminary positive) rapid tests. In late 2005, an unexpected increase in the number of false-positive oral fluid tests occurred, but the increase subsided after several months. In December 2005, while the cluster of false-positive oral fluid test results was being investigated, the NYC DOHMH Bureau of STD Control suspended oral fluid testing in the clinics for 3 weeks and replaced it with finger-stick whole-blood rapid testing, which produced no false-positive test results. On December 21, 2005, NYC DOHMH resumed oral fluid rapid testing but also introduced the use of immediate follow-up finger-stick whole-blood testing, using a second OraQuick test, after any reactive oral fluid test result. In late 2007, another larger increase in the incidence of false-positive oral fluid rapid test results was observed. The cause for the episodic increases in false-positive oral fluid tests has not yet been determined. NYC DOHMH has again suspended the use of oral fluid testing in STD clinics, and finger-stick whole-blood testing is the only rapid HIV test being used in this setting. These findings underscore the importance of confirming all reactive HIV tests, both from oral fluid and whole-blood specimens. In addition, the results suggest that the NYC DOHMH strategy of following up reactive oral fluid test results with an immediate finger-stick whole-blood test reduced the number of apparent false-positive oral fluid test results and might be a useful strategy in other settings and locations.