Introduction: Fluorescence in situ hybridization (FISH) is a valuable tool in clinical practice of cancer.However, high false positive and negative rates complicate the interpretation of results.Cytology allows rapid and relatively easy detection of malignancy.However, it suffers from poor sensitivity.The performance of cytology can be improved by combination with modem molecular biology techniques.Moreover, FISH may become highly sensitive and specific when combined with morphology.In the present study, we used combination of cytology and FISH to detect various malignancies.Material and Methods: The DuetTM scanning system (BioView Ltd, Rehovot, Israel) allows combined analysis of morphology and FISH by performing multiple scans of a slide under different stains.This approach was applied to 80 blood and bone marrow samples for detecting various hematological malignancies, to 140 urine samples for detecting bladder cancer and to 50 sputum samples for detecting lung cancer.Samples were stained and analyzed morphologically, de-stained and subsequently analyzed by multicolor FISH using commercial and/or home-brew.Results: In all cases, the combination of morphology and FISH showed high sensitivity and specificity.In the hematological samples, the technique allowed more accurate diagnosis by determining the cells lineage carrying chromosomal aberrations.In urine samples 100% of recurrent and newly diagnosed bladder cancers were detected.Sputum analysis diagnosed all lung cancer patients with 100% sensitivity and 89% specificity.Conclusion: The growing knowledge on tumor specific genetic aberrations can be translated to diagnostic pathology by combination of morphology analysis and interphase FISH.This is the only technique available for simultaneous visualization of genetic changes and cell morphology on a single cell level.The combination of cytology and FISH improved the sensitivity and specificity of malignancy detection.We believe that this approach will be highly advantageous in the management of diverse malignancies, including early diagnosis and follow up.