Purpose: To evaluate the work stress related physiological responses in professional male bus drivers in Lahore (Pakistan) (ages: 32-39 years) and comparable age and sex matched controls. Methods: Responses of hypothalamic-pituitary-adrenal (HPA) axis determined by morning cortisol and cardiovascular changes assessed by blood pressure (BP), heart rate (HR) and body mass indexes (BMI) were compared in 78 long and 71 short distance drivers (driving duration: 12-15 years) and 80 control never drivers, on a work and a rest day to assess the cardiovascular risks amongst the groups. Results: On a work day, when compared with controls, cortisol was found significantly elevated in drivers with more pronounced elevation in short compared to long distance drivers. BMI was greater in drivers, particularly, in long compared to short distance drivers. BP indicated significant enhancement in short distance drivers, however, long distance drivers exhibited significant rise in diastolic with no variation in systolic BP. HR elevated, significantly, in drivers with more pronounced elevation in long compared to short distance drivers. None of the parameters varied significantly when drivers, on a rest day, were compared with controls. Conclusions: Both HPA axis and cardiovascular indicators exhibited alterations in bus drivers, during driving, with respect to the rest period and the controls. Longer resting times and physical activities like walking and swimming, following continuous driving schedule, to ensure relief or relaxation during prolonged work periods, are suggested.