Abstract Background Previous studies have demonstrated that induction of heme oxygenase-1 results in weight loss in several rodent models of obesity. However, the specific role of the heme oxygenase-1 metabolite, carbon monoxide (CO), in this response has yet to be established. We recently reported that chronic treatment with CO releasing molecules results in prevention of weight gain in mice fed a high fat diet. In the present study, we sought to determine the effect of chronic CO inhalation on the development and reversal of high fat diet induced obesity. Results CO inhalation at both levels initially resulted in a prevention and reversal of body weight and fat mass over the first 10 weeks of treatment, however, this effect was not sustained. CO inhalation in the prevention groups also had an early effect to lower fasting blood glucose but this effect also was not sustained. Conclusions Our results demonstrate that CO inhalation has a transient effect to prevent and reduce body weight which is not sustained chronically in mice fed a high fat diet. These results suggest that chronic CO inhalation therapy is not an effective treatment to induce long term weight loss.