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Purpose: To evaluate the association between sleeping pill/tranquilizer (SP/T) use and quality of life (QOL) among cancer patients., Patients and Methods: Oncology patients (n = 909) in three Israeli hospitals were interviewed in clinics, day centers and in-patient departments regarding SP/T use in the previous week. Crude and adjusted QOL scores, measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30), were compared in users vs. non-users., Results: Sleeping pill/tranquilizer use was self-reported by 234 (25.7%) participants, but rarely documented in medical charts. Factors associated with SP/T use were female gender (adjusted Odds ratio, OR: 1.79; 95% Confidence interval, CI: 1.22-2.62, age (OR: 4.6; 95% CI: 1.66-12.53 for age 70+), place of birth (OR: 1.97; 95% CI: 1.19-3.26 for Eastern Europe compared with Israel), concomitant use of painkillers (OR: 2.88; 95% CI: 1.97-4.20) and presence of cardiovascular disease (OR: 2.41; 95% CI: 1.48-3.91). Controlling these factors as well as disease status, users had a poorer QOL on all functional scales (p < 0.001) as well as global QOL. Furthermore, users reported increased severity of symptoms, especially fatigue, insomnia, pain, dyspnea and constipation (p < 0.01), compared to non-users., Conclusions: Use of SP/T, reported by one fourth of cancer patients, was associated with substantially poorer QOL and increased severity of symptoms. Causal inference is not possible given the cross-sectional design. Periodic inquiry regarding use of these medications in the Oncology Clinic is recommended since it may identify patients with poor QOL and unmet needs.