The Hemodialysis (HEMO) Study showed that high-dose hemodialysis providing a single-pool Kt/V_urea of 1.71 provided no benefit over a standard treatment providing a single-pool Kt/V_urea of 1.32. Here, we assessed whether the high-dose treatment used lowered plasma levels of small uremic solutes other than urea. Measurements made ≥3 months after randomization in 1281 patients in the HEMO Study showed a range in the effect of high-dose treatment compared with that of standard treatment: from no reduction in the level of p-cresol sulfate or asymmetric dimethylarginine to significant reductions in the levels of trimethylamine oxide (–9%; 95% confidence interval [95% CI], –2% to –15%), indoxyl sulfate (–11%; 95% CI, –6% to –15%), and methylguanidine (–22%; 95% CI, –18% to –27%). Levels of three other small solutes also decreased slightly; the level of urea decreased 9%. All-cause mortality did not significantly relate to the level of any of the solutes measured. Modeling indicated that the intermittency of treatment along with the presence of nondialytic clearance and/or increased solute production accounted for the limited reduction in solute levels with the higher Kt/V_urea. In conclusion, failure to achieve greater reductions in solute levels may explain the failure of high Kt/V_urea treatment to improve outcomes in the HEMO Study. Furthermore, levels of the nonurea solutes varied widely among patients in the HEMO Study, and achieved Kt/V_urea accounted for very little of this variation. These results further suggest that an index only on the basis of urea does not provide a sufficient measure of dialysis adequacy.