Background <p>Fospropofol disodium is a water-soluble prodrug of propofol, with a significantly longer time to sedation than propofol. This prospective randomized controlled study aimed to evaluate the effect of adding sufentanil to fospropofol disodium during induction of general anesthesia on sedation quality in elderly patients.</p> Methods <p>One hundred and fifty elderly patients scheduled for elective surgery under general anesthesia were randomly assigned 1:1 to receive either fospropofol disodium (F group) or sufentanil combined with fospropofol disodium (S + F group) (<i>n</i> = 75 each). Patients randomized to F group received fospropofol disodium 10–15&#xa0;mg/kg within 1&#xa0;min for anesthesia induction. Patients randomized to S + F group received sufentanil 0.2–0.4&#xa0;µg/kg, followed by fospropofol disodium within 1&#xa0;min. The primary outcome was time to loss of consciousness, defined as the time to a Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) score of 1 after administration of fospropofol disodium. Secondary outcomes included sedation success rate and hemodynamic parameters. Safety outcomes included the incidence of adverse reactions such as injection pain, pruritus, and paresthesia.</p> Results <p>Compared to the F group, the S + F group had a significantly shorter time to loss of consciousness (91.00 [70.00, 112.00] s vs. 142.50 [121.00, 192.25] s, <i>P</i> &lt; 0.001) and a higher sedation success rate (100% [75/75] vs. 90.7% [68/75], <i>P</i> = 0.020). The incidence of pruritus and paresthesia was significantly lower in the S + F group than in the F group (<i>P</i> &lt; 0.05).</p> Conclusion <p>In elderly patients undergoing general anesthesia, the combination of sufentanil and fospropofol disodium significantly shortened the time to loss of consciousness, improved sedation success and reduced the incidence of adverse reactions compared with fospropofol disodium alone.</p>