The list of standard abbreviations for JDS is available at adsa.org/jds-abbreviations-24. Nonstandard abbreviations are available in the Notes. An experiment was conducted to identify the factors that cause reduced production of cows fed a diet with high content of corn distillers grains with solubles (DDGS). We hypothesized that the factors could be high sulfur (S) content in DDGS, which may directly (S toxicity) or indirectly (DCAD) cause reduced production. We also hypothesized that high PUFA in DDGS could be another major factor. In a randomized complete block design, 60 lactating cows (15 primiparous and 45 multiparous; average ± SD at the beginning of the trial: milk yield, 44.0 ± 6.9 kg/d; DIM, 123 ± 50; BW, 672 ± 82 kg) were blocked, and cows in each block were randomly assigned to 1 of the following treatments: SBM (4.7% fatty acids [FA], 0.22% S, and 178 mEq/kg DM of DCAD), a diet containing soybean meal as the main protein source; DG, with SBM replacing mainly soybean byproducts and supplemental fat with distillers grains at 30% dietary DM (4.7% FA, 0.44% S, and 42 mEq/kg DM of DCAD); SBM+S, SBM with sodium bisulfate for additional dietary S (4.8% FA, 0.37% S, and 198 mEq/kg DM of DCAD); SBM+CO, SBM with corn oil (4.7% FA, 0.23%, and 165 mEq/kg DM of DCAD); and DG+DCAD, DG with increased DCAD (4.7% FA, 0.40% S, and 330 mEq/kg DM of DCAD). Due to the limited number of tiestalls, blocks 1 to 6 started the experiment first as phase 1, and the rest of the blocks, as phase 2, started the experiment after phase 1. All cows were fed the SBM diet for 10 d as a covariate period followed by the experimental period for 35 d. Data were analyzed using PROC MIXED of SAS (Version 9.4, SAS Institute Inc.); block and phase were random effects; and treatments, repeated week, and interaction were fixed effects. We found an interaction of week by treatment for DMI. Although milk yield did not change, milk fat concentration tended to decrease (2.78% vs. 3.34%) for DG compared with SBM. Dry matter, OM, NDF, and CP digestibilities were lower when cows were fed the DG diet compared with SBM. Additionally, cows fed DG had lower blood concentrations of HCO 3 −, base excess, and total (t)CO 2 compared with SBM. The SBM+S diet did not affect production, nutrient digestibility, or blood parameters compared with SBM. The SBM+CO diet decreased milk fat concentration and yield compared with SBM. The DG+DCAD diet tended to increase milk fat yield and concentration (1.24 vs. 1.47 kg/d; 2.78% vs. 3.37%) and increased ECM (40.9 vs. 45.1 kg/d) compared with DG but did not improve nutrient digestibility. However, blood HCO 3 −, base excess, and tCO 2 were greater for DG+DCAD compared with DG. In conclusion, the indirect role of S−, altering DCAD, along with the high PUFA content in DDGS, appear to be the factors causing reduced production responses to a high DDGS diet. Increasing DCAD to 300 mEq/kg DM in a high DDGS diet can be a feeding strategy to alleviate reduced production responses. [ABSTRACT FROM AUTHOR]