Background: There are potential severe effects when patients taking opioids receive other psychoactive medications. However, such combinations are sometimes necessary in palliative care. The purpose of this study was to determine the frequency of concomitant use of opioids + psychoactive medications in cancer patients referred to our outpatient palliative care center. Methods: Retrospective data obtained from consecutive consults was analyzed to determine the frequency of patients on opioids alone versus concomitant opioids + psychoactive medications at first presentation to our clinic. Association of type of medication with demographics and baseline characteristics was evaluated by Wilcoxon rank sum test for continuous variables and Chi-square (Fisher's exact) test for categorical variables. Results: Among 541 consecutive consult visits, 365 (67%) patients were taking opioids at the time of referral to our clinic: 209 (57%) were on opioids alone while 156 (43%) were on concomitant opioids + psychoactive medications [69 (44%) were on Opioid + Benzodiazepine, 46 (30%) were Opioid + Antidepressants, 41(26%) were on both). Patients in the concomitant groups were on higher Morphine Equivalent Daily Dose (MEDD, p = 0.007), had higher Edmonton Symptom Assessment Scores (ESAS) for pain (p = 0.017), anxiety (p < 0.001), depression (p < 0.001) and spiritual pain (p = 0.03). Conclusions: A large proportion (156, 43%) of cancer patients referred to outpatient palliative care was on concomitant opioids + psychoactive medications. These patients were on higher doses of opioids with higher levels of pain and psycho-social distress at the time of first presentation. Further studies are required to better understand the clinical implications of concomitant use of opioids + psychoactive medications in such patients.