Background: It has been hypothesized that certain Mycoplasma species may cause Gulf War veterans’ illnesses (GWVIs), chronic diseases characterized by pain, fatigue, and cognitive symptoms, and that affected patients may benefit from doxycycline treatment. Objective: To determine whether a 12 month course of doxycycline improves functional status in Gulf War veterans with GWVIs. Design: A randomized, double blind, placebo controlled clinical trial with 12 months of treatment and 6 additional months of follow up. Setting: 26 U.S. Department of Veterans Affairs and 2 U.S. Department of Defense medical centers. Participants: 491 deployed Gulf War veterans with GWVIs and detectable Mycoplasma DNA in the blood. Intervention: Doxycycline, 200 mg, or matching placebo daily for 12 months. Measurements: The primary outcome was the proportion of participants who improved more than 7 units on the Physical Component Summary score of the Veterans Short Form 36 General Health Survey 12 months after randomization. Secondary outcomes were measures of pain, fatigue, and cognitive function and change in positivity for Mycoplasma species at 6, 12, and 18 months after randomization. Results: No statistically significant differences were found between the doxycycline and placebo groups for the primary outcome measure (43 of 238 participants vs. 42 of 243 participants ; difference, 0.8 percentage point [95% CI, 6.5 to 8.0 percentage points]; P > 0.2) or for secondary outcome measures at 1 year. In addition, possible differences in outcomes at 3 and 6 months were not apparent at 9 or 18 months. Participants in the doxycycline group had a higher incidence of nausea and photo sensitivity. Limitations: Adherence to treatment after 6 months was poor. Conclusion: Long term treatment with doxycycline did not improve outcomes of GWVIs at 1 year. Background: It has been hypothesized that certain Mycoplasma species may cause Gulf War veterans’ illnesses (GWVIs), chronic diseases characterized by pain, fatigue, and Cognitive symptoms, and that affected patients may benefit from doxycycline treatment. Objective: It determines whether a 12 month course of doxycycline improves functional status in Gulf War veterans with GWVIs. Design: A randomized, double blind, placebo controlled clinical trial with 12 months of treatment and 6 additional months of follow up. Setting: 26 US Department of Veterans Affairs and 2 US Participants: 491 deployed Gulf War veterans with GWVIs and detectable Mycoplasma DNA in the blood. Intervention: Doxycycline, 200 mg, or matching placebo daily for 12 months. Measurements: The primary outcome was the proportion of participants who improved more than 7 units on the Physical Component Summary score of the Veterans Short Form 36 General Health Survey 12 months afte R randomization. Secondary outcomes were measures of pain, fatigue, and cognitive function and change in positivity for Mycoplasma species at 6, 12, and 18 months after randomization. Results: No statistically significant differences were found between the doxycycline and placebo groups for the primary difference, 0.8 percentage point [95% CI, 6.5 to 8.0 percentage points]; P> 0.2) or for secondary outcome measures at 1 year. In addition, possible differences in outcomes at 3 and 6 months were not apparent at 9 or 18 months. Participants in the doxycycline group had a higher incidence of nausea and photo sensitivity. Limitations: Adherence to treatment after 6 months was poor. Conclusion: Long term treatment with doxycycline did not improve outcomes of GWVIs at 1 year.