A 2-yr study was conducted to evaluate bell pepper response and honeyvine milkweed control from PRE herbicides, clomazone and trifluralin, applied under polyethylene mulch. Clomazone (0.8 and 1.4 kg ai ha−1) and trifluralin (0.7 and 1.1 kg ai ha−1) were applied alone or in combination. Herbicides were applied after beds were made and before polyethylene mulch was laid, followed by transplanting pepper within hours of herbicide application. In both years, initial bleaching of lower leaves was observed; the injury was observed in some treatments, but not others. Honeyvine milkweed, growing in the planting hole, exhibited significant bleaching and stunting in most herbicide treatments. Both clomazone and trifluralin resulted in season-long honeyvine milkweed control in both years. However, the use of clomazone and trifluralin together for control of honeyvine milkweed does not seem justified due to the potential for herbicide antagonism, as indicated in this study. The total number and fresh weight of harvested bell pepper were not affected by the herbicides or rates. All herbicide treatments resulted in about twice the yield (average of 8.8 kg) of the hand-weeded control (4.6 kg) in both years. This study strongly supports the safety and effectiveness of clomazone and/or trifluralin applied pretransplant under polyethylene mulch in bell pepper production for control of honeyvine milkweed.