Introduction: Stress responses to work-related stressors often manifest in non-specific physical complaints, by monitoring it may provide early indications of underlying health issues. Hypothesis: We hypothesized that there is a significant association between non-specific physical complaints and the subsequent incidence of cardiovascular diseases (CVD) in middle-aged Japanese. Methods: A cohort of 4820 Japanese workers (3876 male, 944 female) ages 35 to 65 years were followed from 2007 to 2019 for CVD incidence (stroke and acute coronary artery diseases). Non-specific physical complaints were assessed as a domain of stress response in the 57-item brief job stress questionnaire and consisted of 11 items: felt dizzy; experienced joint pains; experienced headaches; had stiff neck or shoulders; had lower back pain; had eyestrain; had heart palpitations or shortness of breath; had stomach or intestine problems; lost appetite; had diarrhea or constipation; couldn’t sleep well. Each item had four possible responses from never, sometimes, often, to always, corresponding scores of which are 1, 2, 3, and 4, respectively. The presence of non-specific physical complaints was defined as a sum score of 27-44 for males and 30-44 for females according to the recommended standard values. Hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) of non-specific physical complaints for CVD were estimated and adjusted for age, sex, smoking status, alcohol consumption, regular exercise, sleep duration, body mass index, systolic blood pressure, total cholesterol, and histories of hypertension, hyperlipidemia, and diabetes. Results: During a median of 10.4 years of follow-up, 90 CVD cases were identified. The presence of non-specific physical complaints was significantly associated with the incidence of CVD independent of confounding variables (HR: 2.04, 95% CI: 1.02-4.07). Conclusion: The present study revealed that the presence of non-specific physical complaints was associated with a higher risk of developing CVD.