This is a 2-year, randomized, two-arm study involving a 6-month period of progressive reduction in the nicotine content of cigarettes. During the first year (tapering/maintenance phases), subjects will smoke progressively reduced nicotine content (RNC) cigarettes over a period of six months, and then remain on the lowest nicotine content cigarette for an additional six months. Comparisons will be made with a control group in which subjects will smoke their usual normal nicotine yield cigarettes. There will be a one year follow-up phase during which subjects will be monitored and will be free to resume smoking a commercial cigarette of their choice, or to quit.

We hypothesize that smokers of cigarettes with progressively reduced nicotine content will experience a reduction in nicotine intake without compensatory oversmoking. This will serve to "wean" them from nicotine and result in a decreased level of nicotine dependence. Once this has occurred, subjects will then be able to maintain their reduced level of nicotine intake for the 6 months that they continue smoking the lowest level RNC cigarette. When they are again free to choose any smoking behavior (follow-up phase), as a result of the period of lowered dependence they will smoke fewer cigarettes and/or have a greater interest in quitting compared to the control group, whose level of nicotine dependence is hypothesized to be sustained throughout.

Primary Hypotheses:

1. Nicotine intake will be lower for the RNC group than for the control group.
2. Exposure to tobacco smoke gas phase constituents will be similar for the RNC and control group.
3. Exposure to tobacco smoke tar constituents will be similar for the RNC and control group.
4. Cardiovascular biomarkers of inflammation, platelet activation, endothelial dysfunction, and HDL cholesterol will be lower for the RNC group than for the control group.
5. Cigarette consumption, as measured by cigarettes-per-day (CPD), will be lower for the RNC group than for the control group.

Secondary hypotheses:

1. Over the course of tapering and maintenance and at follow-up, interest in quitting will be higher in the RNC group compared to the control group.
2. At follow-up, measures of cigarette consumption, nicotine intake, and exposure to tobacco smoke combustion constituents will be lower for the RNC group compared to the control group.

Inclusion Criteria:

• Healthy on the basis of medical history and screening blood tests

• Current moderate-to-heavy smoker as determined by:

  1. smoking more than 10 cigarettes per day regularly for the past year (by history); and
  2. expired CO at screening visit of 25 ppm or more and/or plasma cotinine level of 100 ng/ml or more.
• Age 18-70 years
• Any racial/ethnic background

Exclusion Criteria:

• Expressed desire to quit smoking within 6 months.
• Significant medical conditions (such as anemia, heart disease, uncontrolled hypertension, thyroid disease, diabetes, renal or liver impairment, glaucoma, or prostatic hypertrophy) or psychiatric condition (such as current major depression, history of schizophrenia or bipolar disorder, or current regular use of psychiatric medications such as major tranquilizers and antidepressants). Smokers with uncomplicated controlled hypertension may be enrolled.
• Pregnancy or lactation (by history)
• Current use of smokeless tobacco, pipes or cigars
• Alcohol abuse or illicit drug use (by history)
• Concurrent participation in another clinical trial or prior participation in our pilot studies using the same RNC cigarettes as in these studies