Cognitive and behavioral impairments are common in patients with epilepsy. Multiple factors may contribute to these difficulties; among them is antiepileptic drug (AED) treatment. We examined the short-term impact of two new add-on AEDs, pregabalin (PGB) and levetiracetam (LEV), on cognition and psychiatric states in 20 adult patients with medically refractory partial epilepsy, before and shortly after add-on titration. According to an open, prospective comparative trial, add-on PGB was titrated to 300 mg and add-on LEV to 1000 mg in 10 patients each. Patients were assessed before (T1) and 2 weeks after (T2) addition of the AED. During the trial, seizure frequency did not change significantly in either group. With PGB, patients manifested partly significant impairments in episodic memory of verbal and visual information. Psychiatric states were unchanged. With LEV treatment, we saw improvements in visual short-term memory performance and psychiatric states (i.e., interpersonal sensibility, depression, and anxiety). The comparison between PGB and LEV revealed a trend toward higher anxiety scores and higher variability in hostility scores with PGB that was significantly different from the trend with LEV. No significant differences were apparent in all other neuropsychological and psychiatric parameters investigated. This short-term study suggests that add-on LEV has a favorable neuropsychological and psychiatric impact. The negative neuropsychological effects of PGB may reflect temporary effects under titration. Still, the results did not confirm the promising effects on psychiatric comorbidity that have been emphasized by other reports.