Screening for cyclic antidepressants compounds is a classical toxicology test. Immunological tests are badly known, especially concerning their sensivity and interferences. To investigate which molecules could produce false positive results for cyclic antidepressants screening, we tried to obtain correlations between the test reaction and the three-dimensional structures of the molecules. We studied the Emit^® Tox™ Serum Tricyclic Antidepressants Assay from Siemens on a Dimension^® Xpand^® platform. Four hundred and twenty-six positive or interfering samples were tested thanks to GC, GC/MS or Biorad^® Remedi^®. The known or potential list of interfering compounds allowed us to test these molecules of the immunoassay test with spiked plasmas. Afterwards we measured inter-atomic distances and angles thanks to the 3D module of ChemSketch^® 10.0 software. Out of 426 positive tests, 247 have been identified. Percentage of cross-reactivity has been calculated and finally correlated with molecular structures. A principal component analysis managed to produce analogies so as to gather some molecules on different plans and correlations between the structures and the reactivity percentage could be so obtained. The interferences, known or not, were in a large number. This study allowed us to enlarge screening thanks to other techniques such as GC/NPD, LC/DAD or mass spectrometry in case of doubt on the immunologic results.