Thoracic computed tomography (CT) is a sensitive method for detecting early lung cancer but has a high false-positive rate and is not sensitive for detecting central preinvasive and microinvasive cancer. Our hypothesis was that automated quantitative image cytometry (AQC) of sputum cells as the first screening method may improve detection rate by identifying individuals at highest risk for lung cancer. A total of 561 volunteer current or former smokers 50 years of age or older, with a smoking history of more than or equal to 30 pack/years, were studied. Among these, 423 were found to have sputum atypia defined as five cells or more with abnormal DNA content using AQC. Noncalcified pulmonary nodules were found in 46% (259/561). Of the 14 detected cancers, 13 were detected in subjects with sputum atypia-nine by CT and four carcinoma in situ/microinvasive cancers by autofluorescence bronchoscopy. One cancer was detected by CT alone. AQC of sputum cells improved the detection rate of lung cancer from 1.8 to 3.1%. CT scan alone would have missed 29% of the cancers. This screening paradigm shift has the additional potential of reducing the number of initial CT scans by at least 25% with further savings in follow-up investigations and treatment.