The Agency for Health Care Policy and Research (AHCPR) published the Smoking Cessation: Clinical Practice Guideline in 1996. Based on the results of meta-analyses and expert opinion, the guideline identifies efficacious interventions for primary care clinicians and smoking cessation specialty providers. To determine the cost-effectiveness of clinical recommendations in AHCPR's guideline. The guideline's 15 recommended smoking cessation interventions were analyzed to determine their relative cost-effectiveness. Then, using decision probabilities, the interventions were combined into a global model of the guideline's overall cost-effectiveness. The analysis assumes that primary care clinicians screen all presenting adults for smoking status and advise and motivate all smokers to quit during the course of a routine office visit or hospitalization. Smoking cessation interventions are provided to 75% of US smokers 18 years and older who are assumed to be willing to make a quit attempt during a year's time. Three counseling interventions for primary care clinicians and 2 counseling interventions for smoking cessation specialists were modeled with and without transdermal nicotine and nicotine gum. Cost (1995 dollars) per life-year or quality-adjusted life-year (QALY) saved, at a discount of 3%. The guideline would cost $6.3 billion to implement in its first year. As a result, society could expect to gain 1.7 million new quitters at an average cost of $3779 per quitter, $2587 per life-year saved, and $1915 for every QALY saved. Costs per QALY saved ranged from $1108 to $4542, with more intensive interventions being more cost-effective. Group intensive cessation counseling exhibited the lowest cost per QALY saved, but only 5% of smokers appear willing to undertake this type of intervention. Compared with other preventive interventions, smoking cessation is extremely cost-effective. The more intensive the intervention, the lower the cost per QALY saved, which suggests that greater spending on interventions yields more net benefit. While all these clinically delivered interventions seem a reasonable societal investment, those involving more intensive counseling and the nicotine patch as adjuvant therapy are particularly meritorious.