Women diagnosed with fibromyalgia (N = 72) participated in a 10-week randomized trial to examine the effectiveness of guided imagery on self-efficacy, perceived stress, and selected biobehavioral factors (FMS symptoms; immune biomarkers). Participants in both guided imagery and usual care control conditions completed measures and donated 3 cc of blood at baseline, 6- and 10-weeks. A mixed effects linear model to test for differences between groups for all behavioral and biologic variables demonstrated that after 10 weeks of daily intervention use, guided imagery participants reported statistically significant increases in self-efficacy and statistically significant decreases in stress, fatigue, pain, and depression. There were no statistically significant changes in biomarker levels, although total group C-reactive protein was elevated at baseline (4.7 mg/L), indicating an inflammatory process. Subsequent studies should be undertaken to more fully elucidate the biobehavioral aspects of nonpharmacological intervention effectiveness.