The study aimed to identify the extent of smoking, compliance with tobacco restrictions, and attitudes toward smoking and tobacco control measures among the employees in a Comprehensive Cancer Center from 2001 to 2006 where a smoke-free policy was progressively introduced. Four cross-sectional surveys were conducted from 2001 to 2006. Survey items include smoking status, smoking history, environmental tobacco exposure, and agreement with tobacco initiatives. The prevalence of smoking has declined from 34.5% in 2001 to 30.6% in 2006. The decrease was present in all professional groups: Doctors from 20.0% in 2001 to 15.2% in 2006 and administrative clerks from 56.0% in 2001 to 37.0% in 2006 reduced the most. Among nurses, the prevalence of smoking was still high with a 2-point percent reduction (from 34.0% in 2004 to 32.6% in 2006). Other changes of the pattern of smoking were apparent: a reduction on the number of cigarettes smoked, decrease of daily smokers, and increase of smoking abstinence during the hospital duty. Compliance with smoke-free areas increased. We observed a very significant decrease of the perception of exposure to environmental tobacco exposure at work. The Smoke Free project helped to achieve a healthy work environment. Tailored smoking cessation programs should be designed to help healthcare professionals to stop smoking. In addition, healthcare professionals should play a key role in promoting a healthy smoke-free lifestyle.