Smoking-related cancer and other disease account for more than 400,000 U.S. deaths annually. Smoking cessation reduces smoking-related disease rates, but relapse rates are high. Thus, interest in reducing the harm of continued smoking is growing. Potential reduced exposure products (PREPs) are marketed to reduce smokers' exposure to smoke toxicants such as carbon monoxide (CO) and carcinogens and may be harm reduction tools. New PREPs are proliferating, but past experience with “low-yield” cigarettes that failed to reduce smokers' toxicant exposure suggests that comprehensive evaluation is necessary to predict if these new products are likely to alter the harm caused by smoking. The purpose of the study was to develop clinical laboratory methods for PREP evaluation. Smokers (N = 35) completed four, 5-day conditions that differed by product used: Advance, Eclipse, own brand cigarettes, or no cigarettes. Carcinogen (as assessed by one nitrosamine and one polycyclic aromatic hydrocarbon biomarker) and nicotine exposure were assessed via thrice-weekly urine sampling. Withdrawal symptoms were measured daily, and smoking behavior was assessed on the first and last day of each condition. Relative to own brand, Advance reduced exposure to the nitrosamine NNK and CO, and Eclipse reduced exposure to nicotine and the nitrosamine NNK, increased exposure to CO, and resulted in larger, longer, and more frequent puffs. No smoking reduced exposure to the nitrosamine NNK, CO, and nicotine, whereas withdrawal was elevated (all p values <.05). Clinical laboratory evaluation of PREPs for smokers is valuable for measuring users' smoke toxicant exposure, withdrawal, and smoking behavior and should be incorporated into a comprehensive PREP evaluation strategy.