Although the effect of smoking cessation on weight gain is well-documented, little is known about the effect of weight loss on smoking. We examined the association between saliva cotinine levels and weight loss in a group of 9 obese female smokers during participation in a protein-sparing modified fast (Optifast). For the first 3 months of treatment, subjects consumed only the protein-sparing supplement; for the next 3 months, food was gradually reintroduced. Body mass index and saliva cotinine concentration were assessed at study entry and at 3 and 6 months. A significant weight loss was noted at 3 and 6 months, yet the cotinine level increased significantly over this time. It is unclear whether the cotinine increase is due to metabolic changes or an actual increase in nicotine intake. The results suggest that smoking-related health risks may increase during periods of significant weight loss.