Epilepsy patients are more likely to experience depressive symptoms and cognitive impairment compared to individuals in the general population. As the reasons for this are not definitively known, we sought to determine what factors correlate most strongly with cognition and a screening test for depression in epilepsy patients. Methods: Our study population included 379 adult patients diagnosed with epilepsy or seizure in our neurology clinic. We collected detailed demographic and clinical data during patient visits using structured clinical documentation support tools that we have built within our commercial electronic medical records system (Epic), including a depression score (Neurological Disorders Depression Inventory for Epilepsy, NDDIE) and cognition score test measures (specifically in this study, Mini-Mental State Examination [MMSE]). Medication, age, gender, body mass index, duration of epilepsy, seizure frequency, current number of anti-epileptic medications, years of education were assessed in relation to baseline score as well as change in score from initial visit to first annual follow-up. Results: Of the analyzed factors, two statistically significant associations were found after correction for multiple testing. Male gender and lower anti-seizure medication count were associated with better mood, as assessed by NDDIE score, at initial visit. Specifically, male gender was associated with a 1.3 decrease in NDDIE and for each additional anti-seizure medication, there was an associated 1.2 increase in NDDIE. Conclusions: However, these factors were not associated with change in NDDIE score from initial to first annual follow-up visit. These findings, although interesting, are preliminary. Additionally, these findings were based on a homogenous (mainly Caucasian) clinic-based population and detailed information on previous medication use was lacking. Further work is needed to replicate these findings and to understand any mechanisms that may explain these associations.