Atherosclerosis is an inflammatory disease. The study was aimed to investigate the association between job strain and inflammation markers and to examine factors contributing to high strain. The long-haul bus drivers (n = 825) were recruited from a Taiwanese transportation company. The psychosocial work environment was measured by a validated job content questionnaire (JCQ). Plasma high sensitivity C-reactive protein (hs-CRP) and homocysteine (Hcy) were analyzed as inflammation markers. Job strain effects and its interaction with age were analyzed by logistic regression. Explained variance (Nagelkerke R square) was applied to select important stressors. The crude and adjusted odds ratio (OR) for the effect of high strain on high hs-CRP and Hcy were not significant. However, there was significant interaction between job strain and age (p = .014). The significantly increased risk of high strain on high hs-CRP was found among drivers younger than 35 years old (OR = 2.71), but not in driver groups age 35 to 49 and older than 50. The contributing factors to high strain were varied among the 3 age groups. The 3 stressors found for young drivers were having rest time less than 8 hours between 2 shifts, being physically inactive during leisure time, and frequent driving more than 12 hours a day. Job strain interacted with age influenced hs-CRP levels. The risk of inflammatory disease markers only increased in high strained group of young drivers. Appropriate work shift systems should be implemented to increase off-duty time, reduce sleep restrictions, and increase physical activity during leisure time.