Systematic review of literature focused on heterogeneity of treatment effect analysis. The objectives of this systematic review were to determine if comorbid disease and general health factors modify the effect of fusion versus nonoperative management in chronic low back pain (CLBP) patients? Surgical fusion as a treatment of back pain continues to be controversial due to inconsistent responses to treatment. The reasons for this are multifactorial but may include heterogeneity in the patient population and in surgeon's attitudes and approaches to this complex problem. There is a relative paucity of high quality publications from which to draw conclusions. We were interested in investigating the possibility of detecting treatment response differences comparing fusion to conservative management for CLBP among subpopulations with different disease specific and general health risk factors. A systematic search was conducted in MEDLINE and the Cochrane Collaboration Library for literature published from 1990 through December 2010. To evaluate whether the effects of CLBP treatment varied by disease or general health subgroups, we sought randomized controlled trials or nonrandomized observational studies with concurrent controls evaluating surgical fusion versus nonoperative management for CLBP. Of the original 127 citations identified, only 5 reported treatment effects (fusion vs. conservative management) separately by disease and general health subgroups of interest. Of those, only two focused on patients who had primarily back pain without spinal stenosis or spondylolisthesis. Few studies comparing fusion to nonoperative management reported differences in outcome by specific disease or general health subpopulations. Among those that did, we observed the effect of fusion compared to nonoperative management was slightly more favorable in patients with no additional comorbidities compared with those with additional comorbidities and more marked in nonsmokers compared with smokers. It is unclear from the literature which patients are the best candidates for fusion versus conservative management when experiencing CLBP without significant neurological impairment. Nonsmokers may be more likely to have a favorable surgical fusion outcome in CLBP patients. Comorbid disease presence has not been shown to definitively modify the effect of fusion. Further prospective studies that are designed to evaluate these and other subgroup effects are encouraged to confirm these findings. We recommend optimizing the management of medical co-morbidities and smoking cessation before considering surgical fusion in CLBP patients. Strength of recommendation: Weak.