Importance There is a paucity of controlled treatment trials for the treatment of conversion disorder, seizures type, also known as psychogenic nonepileptic seizures (PNES). Psychogenic nonepileptic seizures, the most common conversion disorder, are as disabling as epilepsy and are not adequately addressed or treated by mental health clinicians. Objective To evaluate different PNES treatments compared with standard medical care (treatment as usual). Design, Setting, and Participants Pilot randomized clinical trial at 3 academic medical centers with mental health clinicians trained to administer psychotherapy or psychopharmacology to outpatients with PNES. Thirty-eight participants were randomized in a blocked schedule among 3 sites to 1 of 4 treatment arms and were followed up for 16 weeks between September 2008 and February 2012; 34 were included in the analysis. Interventions Medication (flexible-dose sertraline hydrochloride) only, cognitive behavioral therapy informed psychotherapy (CBT-ip) only, CBT-ip with medication (sertraline), or treatment as usual. Main Outcomes and Measures Seizure frequencywas the primary outcome; psychosocial and functioning measures, including psychiatric symptoms, social interactions, quality of life, and global functioning, were secondary outcomes. Data were collected prospectively, weekly, and with baseline, week 2, midpoint (week 8), and exit (week 16) batteries. Within-group analyses for each arm were performed on primary (seizure frequency) and secondary outcomes from treatment-blinded raters using an intention-to-treat analysis. Results The psychotherapy (CBT-ip) arm showed a 51.4%seizure reduction (P = .01) and significant improvement from baseline in secondary measures including depression, anxiety, quality of life, and global functioning (P < .001). The combined arm (CBT-ip with sertraline) showed 59.3%seizure reduction (P = .008) and significant improvements in some secondary measures, including global functioning (P = .007). The sertraline-only arm did not show a reduction in seizures (P = .08). The treatment as usual group showed no significant seizure reduction or improvement in secondary outcome measures (P = .19). Conclusions and Relevance This pilot randomized clinical trial for PNES revealed significant seizure reduction and improved comorbid symptoms and global functioning with CBT-ip for PNES without and with sertraline. There were no improvements in the sertraline-only or treatment-as-usual arms. This study supports the use of manualized psychotherapy for PNES and successful training of mental health clinicians in the treatment. Future studies could assess larger-scale intervention dissemination. Trial Registration clinicaltrials.gov Identifier: NCT00835627.