Objective To explore the sedative effects of S-ketamine combined with dexmedetomidine or midazolam in patients undergoing urinary endoscopy. Methods The clinical data of 68 patients with urinary endoscopy were retrospectively analyzed. The patients with sedation regimen of S-ketamine combined with dexmedetomidine were included in group D (n=37), and patients with S-ketamine combined with midazolam were included in group M (n=31). The vital signs ［heart rate (HR), mean arterial pressure (MAP), blood oxygen saturation (SpO2)］ were compared between the two groups after entering the room (T1), at the end of administration (T2), at 15 min of examination (T3) and at the end of examination (T4). The differences of relevant examination indicators and incidence rate of adverse drug reactions were analyzed in the two groups. Results At T2, T3 and T4, the HR levels in the two groups were significantly lower than those at T1 (P＜0.05), but there was no significant difference between the two groups at the same time (P＞0.05). The levels of MAP and SpO2 in group D were not significantly changed compared with those at T1 (P＞0.05), but they were significantly higher than those in group M at the same time (P＜0.05). There were no significant differences in the duration of examination and incidence rates of nausea/vomiting and delirium between the two groups (P＞0.05). The S-ketamine dosage, body recovery time, departure time from room and incidence rates of bradycardia and respiratory depression in group D were significantly less than those in group M (P＜0.05). Conclusion S-Ketamine combined with dexmedetomidine can increase the stability of vital signs in patients with urinary endoscopy. The safety of this sedative drug regimen is ideal, which is beneficial to the rapid body recovery after examination.