Purpose Cancer patients are often prescribed antidepressants, but little data is available about whether the type and dose are similar to prescriptions to patients with other chronic diseases. This study compared the prescription practices of antidepressants to cancer and non-cancer inpatients at a major Australian tertiary hospital and assessed side effects and potential drug interactions. Methods Inpatients diagnosed with cancer within the past 12 months and prescribed antidepressants were age and gender matched to inpatients with other chronic disease conditions. Data from 75 cancer and 75 non-cancer inpatients were extracted. Results Antidepressants were prescribed to cancer and noncancer patients, respectively, for the treatment of depression (n = 50 vs n = 59), other mental health problems (n = 8 vs n = 11, p < 0.67) or unspecified reasons (n = 17 vs n = 5, p < 0.02). Mirtazapine (n = 11/75) was most commonly prescribed to cancer patients followed by duloxetine (n = 9/75). Desvenlafaxine (n = 15/75) was prescribed most commonly to non-cancer inpatients, followed by mirtazapine (n = 11/75). Four cancer patients and three non-cancer patients had documented adverse side effects from antidepressants. About one third of cancer patients (n = 23/75) and about a quarter of noncancer patients (n = 18/75) were prescribed other medicines with the potential for drug-drug interactions with antidepressants. Conclusions Antidepressants were prescribed for a range of indications in all patients, but more commonly for unspecified reasons among the cancer patients. Future prospective studies that monitor antidepressant prescribing to cancer patients should ascertain details of the indication, pathways to prescription and differences in type, dose or schedule depending on prescribing medical practitioner.