Purpose: Polypharmacy has been associated with drug-drug interactions, adverse drug events, hospitalisation and increased mortality. The purpose of this study was to investigate the prevalence and factors associated with polypharmacy in older people with cancer. Patients and methods: Patients aged =70 years (n=385) presenting to the medical oncology outpatient clinic at Royal Adelaide Hospital between January 2009 and July 2010 completed a structured data collection instrument. The instrument included domains related to medications, diagnoses, instrumental activities of daily living (IADLs), Karnofsky Performance Scale (KPS), physical function (SF-36), pain (ten-point visual analogue scale, VAS), weight loss (patient self-reported over previous 6 months), exhaustion (CES-D) and distress (ten-point VAS). Frailty was computed using Fried s frailty phenotype. Logistic regression was used to compute unadjusted and adjusted odds ratios (ORs) and 95 confidence intervals (CIs) for the association between polypharmacy (defined as five or more self-reported daily medications) and clinical parameters. Results: Polypharmacy was present in 57 (n=221) of patients. When adjusting for age, gender and Charlson Comorbidity Index (CCI), polypharmacy was associated with being pre-frail (OR=2.35, 95 CI=1.43-3.86) and frail (OR=4.48, 95 CI=1.90-10.54) compared to being robust. When adjusting for age, gender, exhaustion, KPS, IADLs, pain and distress, polypharmacy was associated with higher CCI scores (OR=1.58, 95 CI=1.29-1.94) and poorer physical function (OR=1.13, 95 CI=1.06-1.20). Conclusions: Polypharmacy is highly prevalent in older people with cancer and associated with impaired physical function and being pre-frail and frail compared to being robust. Research is needed to identify strategies to minimize patients medication regimens.