Abstract: Objective To explore the safety of one-stage bilateral unicompartmental knee arthroplasty (OB-UKA). Methods A total of 35 patients who underwent OB-UKA at Nanjing Drum Tower Hospital from January 2021 to January 2023 were selected and their clinical data were retrospectively analyzed. Meanwhile, another 35 age- and gender-matched patients each from those who underwent unilateral UKA and unilateral total knee arthroplasty (TKA) were selected as controls. The three groups were compared for surgery-related indicators (operation time, total blood loss, and the length of hospitalization stay), nutritional status 〔hemoglobin (Hb) and albumin (ALB)〕, inflammatory markers 〔white blood cell count (WBC) and C-reactive protein (CRP)〕, pain levels, knee function scores, and complications. Results There were no statistical differences in general information among the three groups before surgery. The OB-UKA group showed longer operation time than the UKA and TKA groups (P<0.05). The OB-UKA group also presented significantly higher total blood loss than the UKA group, without statistical difference compared with the TKA group (P>0.05). There were no statistical differences in postoperative Hb and ALB between the OB-UKA and UKA groups (P>0.05). There were no statistical differences in postoperative WBC and CRP between the OB-UKA and TKA groups(P>0.05). The postoperative visual analog scale (VAS) score in the OB-UKA group showed no significant difference from the UKA group but was significantly lower than the TKA group (P<0.05). The Hospital for Special Surgery (HSS) knee function score of the OB-UKA group was comparable to the UKA group but significantly higher than the TKA group (P<0.05). The incidence of complications in the UKA and OB-UKA groups was 2.9% each, both lower than 5.7% observed in the TKA group (P<0.05). Conclusions Compared with UKA, OB-UKA is associated with longer operation time and increased blood loss. However, its postoperative nutritional indicators are similar to those of the UKA group, with reduced pain levels and comparable functional outcomes. Additionally, postoperative inflammatory markers in the OB-UKA group are similar to those in the TKA group, with a perioperative complication rate comparable to UKA and lower than TKA. OB-UKA can be considered a safe and effective surgical option for patients with bilateral compartment degeneration.