Field and greenhouse studies were conducted to determine the influence of soil organic matter on herbicidal activity using four Pocomoke soils with organic matter contents of 4.8, 7.0, 11.9, and 17.0%. In field experiments, control of giant green foxtail [Setaria viridis var. major (Gaud.) Posp.] was greater than 75% from all treatments of 2-chloro-2′,6′-diethyl-N-(methoxymethyl) acetanilide (alachlor), 2-chloro-N-isopropylacetanilide (propachlor), and N,N-diallyl-2-chloroacetamide (CDAA) with no statistical differences between chemicals, rates, or organic matter levels. Control was statistically lower from all 2-chloro-4-(ethylamino)-6-(isopropylamino)-s-triazine (atrazine) treatments except 2.6 kg/ha at 7% organic matter and 4.4 kg/ha at 7 and 17% organic matter. Under greenhouse conditions, giant foxtail (Setaria faberi Hermm.) was used to establish GR50 values on soils or soil mixtures containing 0.8, 1.9, 3.9, 6.4, 11.0, and 18.7% organic matter for the herbicides used in the field study and for 2-chloro-N-(1-methyl-2-propynyl)acetanilide (prynachlor). Generally as organic matter levels increased, the GR50 values for herbicides increased; the rate of GR50 increase varied with herbicides. A ranking of herbicides from most toxic to least toxic is: propachlor>alachlor>prynachlor>CDAA. Atrazine GR50 values varied from a low similar to propachlor at 0.8% organic matter to 20 times greater than propachlor at 17% organic matter.