An 8-year-old male neutered 37.4 kg mixed breed dog was presented for suspected ingestion of a large amount of naproxen (estimated at 235-294 mg/kg). The dog was treated using a combination of therapeutic plasma exchange (TPE) and plasmaperfusion (PP). The exchange of 2 plasma volumes during 140 min of TPE resulted in a 46% decrease in blood naproxen concentration. Treatment of 1 plasma volume during the following 90 min of PP resulted in an additional 10.3% decrease in naproxen concentration. The patient developed mild gastrointestinal (GI) signs that were treated medically and was successfully discharged after 4 days of hospitalization with normal follow-up laboratory test results and physical examination findings. The combination of extracorporeal treatments decreased the plasma concentration of naproxen, but the additional decrease from PP may not have provided substantial benefit compared with other conventional treatments. No reports of PP, as an alternative to hemoperfusion (HP), in veterinary medicine currently are available.