Water smartweed, an uncommon but troublesome perennial weed of the knotweed family (Polygonaceae), has been endemic with its terrestrial growth form in the area of Kato Nevrokopi in northern Greece, one of the most important potato-growing areas of the country. Two field trials were conducted in 2011 to study the response of water smartweed, wild buckwheat (an annual weed also of the knotweed family), and two potato cultivars (‘Agria' and ‘Banba') to various mixtures of metribuzin and pendimethalin, the two most commonly used herbicides for PRE weed management in potato in Greece. Herbicide mixtures consisted of pendimethalin plus metribuzin, pendimethalin plus rimsulfuron, metribuzin plus rimsulfuron, metribuzin plus prosulfocarb, metribuzin plus flufenacet, and pendimethalin plus metribuzin plus rimsulfuron applied preemergence. Metribuzin and pendimethalin were also applied alone. Water smartweed was difficult to control at the treatments and rates tested. Among all mixtures, a premixture of metribuzin plus prosulfocarb at 320 + 3,200 g ai ha−1 provided the greatest control of water smartweed (47%) and wild buckwheat (87%). Herbicide treatments did not cause detrimental effect on growth of either potato cultivar, and marketable tuber yield generally improved with application of mixtures when compared with metribuzin or pendimethalin applied alone. Control of water smartweed in northern Greece potato production remains a difficult problem to solve, suggesting that until new herbicides are registered for use in potato in Greece, other options of weed control should be sought.