Background: Pain is a debilitating side effect that remains poorly controlled in ~50% of cancer patients. Data from the general population has shown a strong bi-directional relationship between sleep disturbance and pain; however, little is known about this relationship in cancer patients. The present secondary analyses examine the effect of pre-RT moderate-severe cancer-related sleep disturbance (CRSD) on subsequent RT-induced pain. Methods: Analyses were performed on 676 female breast cancer patients (mean age 58) scheduled to receive RT from a previously completed multicenter, phase II RCT examining the efficacy of oral curcumin on radiation dermatitis. The trial was conducted at 21 community oncology practices throughout the U.S. affiliated with the URCC NCORP Research Base. CRSD and total pain as well as the subdomains: sensory pain (SP), affective pain (AP), and perceived pain intensity (PPI) were assessed at pre-RT (baseline) and post-RT by the modified MD Anderson Symptom Inventory and the short-form McGill Pain Questionnaire, respectively. Patients were dichotomized into 2 groups: those with moderate-severe CRSD at baseline (N = 101) vs. those with mild or no CRSD (control; N = 575). Results: Spearman rank correlations showed that changes in CRSD from baseline to post-RT were significantly correlated with concurrent changes in total pain, SP, AP, and PPI (r = 0.21–0.38; all p’s < 0.001). Generalized linear estimating equations, after controlling for baseline pain and other covariates (baseline fatigue and distress, age, sleep medications, anti-anxiety/depression medications, prescription pain medications, and depression or anxiety disorder), showed that patients with moderate-severe CRSD at baseline had significantly higher mean values of post-RT total pain (by 39%; p = 0.033), SP (by 41%; p = 0.046), and AP (by 55%; p = 0.035) than the control group, but not for PPI (p = 0.066). Conclusions: These findings suggest that moderate-severe disturbed sleep prior to RT is an important predictor of pain at post-RT in breast cancer patients. Further research is needed to confirm these findings. NCI UG1CA189961, NCATS TL1 TR002000. Clinical trial information: NCT01246973