The in vitro study of sitafloxacin against carbapenem-resistant (CR) Acinetobacter baumannii demonstrated activity against most strains of CR A. baumannii, and the combination of colistin and sitafloxacin showed an in vitro synergistic effect against CR A. baumannii. This study aimed to compare efficacy and safety between colistin plus sitafloxacin with colistin alone for therapy for CR A. baumannii infection. This randomized controlled trial enrolled 56 patients with CR A. baumannii infection (28/group) during 2018–2021, and the treatment duration was 7–14 days. The study outcomes were 28-day mortality, clinical and microbiological responses, and adverse events. There was no significant difference in 28-day mortality between groups (32.1% combination vs. 32.1% monotherapy, p = 1.000). Favorable clinical response at the end of treatment was comparable between groups (81.5% combination vs. 77.8% monotherapy, p = 0.788). Microbiological response at the end of treatment was also comparable between groups (73.1% combination vs. 74.1% monotherapy, p = 0.934). Acute kidney injury was found in 53.8% of the combination group, and in 45.8% of the monotherapy group (p = 0.571). In conclusion, there was no significant difference in 28-day mortality between the colistin monotherapy and the colistin plus sitafloxacin groups. There was also no significant difference in adverse events between groups.