A field trial was conducted for 3 yr (2005 through 2007) near Scottsbluff, NE, to examine weed control, crop safety, forage production, and economics of glyphosate-tolerant and conventional alfalfa establishment systems. Glyphosate applied to alfalfa at the unifoliate growth stage provided 67% weed control and was similar to imazamox applied at the two-trifoliate leaf stage. Delaying glyphosate application until alfalfa had reached the two-trifoliate growth stage improved weed control to 83%, and weed control was similar to imazamox plus 2,4-DB and imazethapyr plus 2,4-DB. Imazamox and imazethapyr caused minor crop injury, and the addition of bromoxynil or 2,4-DB to both herbicides further decreased crop safety. Weeds were most competitive with the first forage harvest and reduced relative feed value, crude protein, and value (dollars per t) of forage compared to forage that had been treated with herbicides. The total forage yield for the season consisted of three forage harvests and was greatest when no herbicides were applied. The total forage yield of plots treated with glyphosate at the two-trifoliate growth stage was greater than that of plots treated with imazamox or imazethapyr in combination with bromoxynil. When glyphosate was applied at the two-trifoliate growth stage, seasonal forage yield was similar to forage treated with imazamox, imazethapyr, or both herbicides in combination with 2,4-DB. When herbicide was applied to alfalfa at the two-trifoliate growth stage, the net return from using glyphosate with a glyphosate-tolerant alfalfa variety or utilizing imazamox with a conventional alfalfa variety were similar at $742 and $743/ha, respectively.