Background: Patients with chronic fatigue syndrome (CFS) have been faced with difficulties in diagnosis and lack of effective treatments. Anecdotal evidence suggests that use of alternative treatments may be common in these patients. Our primary objective was to compare the prevalence and patterns of alternative medicine use among twins who met the Centers for Disease Control and Prevention (CDC) CFS criteria to that of their non-CFS co-twins. Secondary goals were to assess how often alternative medicine use was discussed with physicians and the perceived benefit of these therapies. Methods: Sixty-three twin pairs discordant for CFS completed a survey about their use of 22 alternative therapies. Matched pair odds ratios and 95% confidence intervals were used to examine differences in the use between CFS twins and their non-CFS co-twins. Results: 91% of twins with CFS and 71% of non-CFS twins had used at least 1 alternative treatment in their lifetime. Twins with CFS were more likely to use homeopathy, mega-vitamins, herbal therapies, biofeedback, relaxation/meditation, guided imagery, massage therapy, energy healing, religious healing by others, and self-help groups than their non-CFS counterparts. A large proportion of all twins found alternative therapies helpful; however, only 42% of those with CFS and 23% of those without CFS discussed their use of alternative medicine with a physician. Conclusions: Individuals with CFS frequently used alternative medical treatments yet rarely communicated this use to their medical doctor. Future research should ascertain the usefulness of alternative practices in the management of CFS.