This study was conducted to evaluate the effects of guided imagery on stress and fatigue in patients undergoing radioactive iodine therapy after thyroidectomy in Korea. Participants were 84 individuals (44 for experimental group and 40 for control group) with thyroid cancer. The experimental group listened to a guided imagery CD once a day for 4 weeks. Global Assessment of Recent Stress and Revised Piper Fatigue Scale were self-administered, and heart rate variability was measured at three time points; prior to intervention (T1), just before intervention (T2) and 1 week later after intervention (T3). Heart rate variability was consisted of Standard Deviation of all NN interval (SDNN), Total Power (TP), Low Frequency (LF), and High Frequency (HF). There were significant decreases in stress (F = 28.45, ? < 0.001) and fatigue (F = 26.17, ? < 0.001) over time in the experimental group compared to the control group. Heart rate variability changed over time in the experimental group relative to the control group; SDNN (F = 6.68, P = 0.002), TP (F = 5.29, ? = 0.006), LF (F = 4.58, P = 0.012), and HF (F = 3.71, ? = 0.026). From the results of this study guided imagery can be recommended as an effective intervention to thyroid cancer patients with stress and fatigue.