Quetiapine is an atypical antipsychotic agent with structural similarities to the tricyclic antidepressants (TCA). We report a case of quetiapine overdose that was initially clinically similar to that of a TCA overdose and caused a false-positive TCA immunoassay. We then analyzed three common TCA immunoassays [Microgenics (formerly Diagnostic Reagents, Inc.) Tricyclics Serum Tox EIA Assay, Syva RapidTest d.a.u., and Biosite Triage Panel for Drugs of Abuse] with quetiapine in solution as well as urine from both an overdose patient and a therapeutic patient. There was significant variation of the cutoff of false-positivity in all three immunoassays. Both the Syva and Microgenics immunoassays tested positive in both the overdose and therapeutic samples and were positive at urine levels of 100 microg/mL and 10 microg/mL, respectively. The Triage immunoassay was negative in solutions up to 1000 microg/mL and negative in both the therapeutic and overdose urine samples. Quetiapine may cause false-positive TCA immunoassay with both therapeutic use and in overdose. Significant variation exists between immunoassays to detect quetiapine as a false-positive test.