Background: Lung cancer is the leading cause of cancer-related mortality linked with smoking, though only 6-18% of heavy smokers die of lung cancer. We hypothesized that major stressful life events are a risk factor for developing lung cancer. Methods: In our matched case-control study, cases (CA) were lung cancer patients diagnosed within past 12 months. Controls (CO) were patients without a prior history of malignancy. CA and CO were matched for age, gender and smoking status. Smokers had at least 10 packs/years history of smoking. Data was collected using standardized research questionnaire on 11 major stressful life events using Holmes and Rahe stress scale. The primary endpoint was odds of having a major stressful life event. A sample of 360 patients (120 CA and 240 CO), was needed to achieve 80% power to detect an odds ratio (OR) of 2.00 using Chi-Square test with a P = 0.05 significance. The study was IRB approved at each institution. Results: Between May 2015 and December 2016, 324 patients were enrolled (23 were excluded due to prior cancer history or incomplete information). 301 (CA = 102; CO = 199) were included in the final analysis. The two groups were well matched in median age (CA = 64.4 years; CO = 63.9years), gender (CA-Male = 48%; CO-Male = 49.2%) and smoking status (ever smoker, CA = 86%; CO = 85%). There was no difference in lifetime stressful life event between CA and CO (95% vs 93.9% P = 0.68%). However, CA were significantly more likely to have had a major stressful life event within the past 5 years than controls (CA = 77.4% vs CO = 65.8%, P = 0.03, (OR = 1.78). Serious life-threatening illness of an immediate family member (P = 0.04) and retirement (P = 0.07) within the past 5 years were noticeably more common among CA. Holmes-Rahe stress score in the last 5 years was higher in men (86.3 vs 63.3, P = 0.07) and those > 65 years old (82.4 vs 57.2,P = 0.04) as compared with CO and in those with squamous histology than with adenocarcinoma (115.6 vs 63.4, P = 0.005). Conclusions: Patients with lung cancer (CA) were significantly more likely to have had a major stressful life event within the past 5 years than the matched controls (CO), especially in older men with squamous histology. Major stressful life events should be considered a risk factor for developing lung cancer.