Fifteen participants were included in this double-blind, cross-over study investigating the dose-related effects of S-ketamine and N,N-dimethyltryptamine (DMT) on prepulse inhibition (PPI) and its attentional modulation in humans. Participants were administered low- and high-dose S-ketamine and DMT intravenously in a pseudorandomized order in two sessions with a washout period of 2 hours between doses and 2-4 weeks between sessions. Startle amplitude, PPI and habituation were calculated using EEG and task performance results from a multi-trial startle session employing both simple and composite trial types (pulse only, prepulse only, pulse plus prepulse or pulse plus postpulse) with varying lead intervals (100 and 240 ms), and task conditions (attended or relaxed). S-ketamine increased PPI at both dosages, whereas DMT had no significant effects. S-ketamine decreased and DMT tended to decrease startle amplitude. There were no significant effects of either drug on the attentional modulation of PPI.