Sulfonamide antimicrobial agents are widely used in human medicine and animal husbandry. These compounds enter soil environments through effluent irrigation and application of manure and sewage biosolids as soil amendments. The primary concern with introducing antimicrobial agents into soil and water environments is the spread of antibiotic resistance in response to increased selective pressure, potentially leading to proliferation of resistant pathogens. The interaction of sulfonamide antimicrobials with soil constituents influences their mobility and bioavailability. Clay minerals and humic substance represent two important sorbent phases in soil that usually occur in association with each other. We examined the sorption and desorption of sulfamethazine to three reference smectite clays with and without humic acid coatings. The smectites were coated at humic acid-to-clay-ratios of 1:5, 1:50 and 1:100. For most humic-clay complexes, aliphatic carbon exhibited greater affinity to the smectites than aromatic carbon at lower humic-to-clay ratios 1:50 and 1:100 as evidenced by infrared and UV-Vis spectra. Both sorption and desorption isotherms of sulfamethazine were well fit with the Freundlich model. Coating clay minerals with humic acid enhanced sulfamethazine sorption, most markedly at the 1:5 humic-to-clay ratio, at which sorption linearity was decreased significantly. Desorption hysteresis was observed and a thermodynamic index of irreversible was calculated. Apparent competitive sorption with another sulfonamide (sulfapyridine) was observed for clays with the highest levels of humic acid coating.