Custom applicators intensively apply herbicides to corn and soybean fields each spring. The primary objective of this study was to characterize the exposure distributions of the herbicides alachlor, atrazine, 2,4-D 2-ethylhexyl ester (2,4-D EH), and metolachlor among a group of applicators during the spring pre-emergent spray season. A secondary objective was to evaluate determinants of exposure and to estimate within- and between-worker variance components. Fifteen applicators were sampled using a systematic design that included spray and non-spray days and multiple measurements (five to seven) on each applicator. Air, patch, and handwash samples were collected on 89 applicator-days. Applicator-days were classified into three categories: target herbicide sprayed, non-target herbicide sprayed, and no herbicide sprayed. Mixed-model regression analysis was used. For all exposure metrics, adjusted mean herbicide exposures were significantly higher on days when target herbicides were sprayed as compared to non-spray days. For 2,4-D EH only, adjusted mean exposures on non-target herbicide spray days were significantly higher than on non-spray days. Wearing gloves significantly reduced adjusted mean hand exposure for all herbicides (4–20 fold) and adjusted mean thigh exposure for three herbicides (8–53 fold) on days the herbicides were sprayed; however, wearing gloves significantly increased adjusted mean atrazine hand and thigh exposures (9 and 7 fold, respectively) on days that non-atrazine herbicides were sprayed. Few of the other covariates were consistent determinants of exposure. For all exposure metrics, the within-worker variability (GSDW 2.1–5.6) was greater than the between-worker variability (GSDB 1.2–2.7).