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Background: An increase in the prevalence of lung cancer that is not smoking-related has been noticed in recent years. Unfortunately, these patients are not included in low dose computer tomography (LDCT) screening programs and are not actually considered in early diagnosis. Therefore, improved early diagnosis methods are urgently needed for non-smokers. It is necessary to establish a prediction model for non-smoking individuals at intermediate to high risk of developing lung cancer (LC) and develop a tool to address the significant gap in evaluating pulmonary nodules in non-smokers. Methods: We retrospectively investigated 1121 patients with pulmonary nodules, who underwent LDCT examinations between September 2019 and March 2023. Five artificial intelligence (AI) algorithms were used to build two kinds of models and identify which one was better at diagnosing non-smoking pulmonary nodules patients. In the first model, we assigned 554 non-smoking individuals to a training cohort and 150 non-smoking patients to an independent validation cohort. The second model included 971 patients for the training set and 150 non-smoking patients for an independent validation set. All LDCT images of participants were obtained for AI analysis. AI of LDCT scans, liquid biopsy, and clinical characteristics were collected for model building. Results: Among LC patients, 58,4% were non-smokers. Non-smoking patients had a high incidence of LC (71.4%), and women showed a significant excess risk compared with non-smoking men in terms of LC risk. Furthermore, our results indicated that the model built using random forest (RF) method, which integrates clinical characteristics (age, extra-thoracic cancer history, gender), radiological characteristics of pulmonary nodules (nodule diameter, nodule count, upper lobe location, malignant sign at the nodule edge, subsolid status), the artificial intelligence analysis of LDCT data, and liquid biopsy achieved the best diagnostic performance in the independent external non-smokers validation cohort (sensitivity 92%, specificity 97%, area under the curve [AUC] = 0.99). Conclusions: These results could significantly improve early non-smoker LC diagnosis and treatment for non-smoker patients with malignant nodules. The established multi-omics model is a noninvasive prediction tool for non-smoking malignant pulmonary nodule diagnosis. Validation revealed that these models exhibited excellent discrimination and calibration capacities, especially the first model built using the RF method, suggesting their clinical utility in the early screening and diagnosis of non-smoking LC. [ABSTRACT FROM AUTHOR]