Background There is insufficient data on the benefits of empiric antibiotic combinations for hospital-acquired pneumonia (HAP). We aimed to investigate whether empiric anti-pseudomonal combination therapy with fluoroquinolones decreases mortality in patients with HAP. Methods This multicenter, retrospective cohort study included adult patients admitted to 16 tertiary and general hospitals in Korea between January 1 and December 31, 2019. Patients with risk factors for combination therapy were divided into anti-pseudomonal non-carbapenem β-lactam monotherapy and fluoroquinolone combination therapy groups. Primary outcome was 30-day mortality. Propensity score matching (PSM) was used to reduce selection bias. Results In total, 631 patients with HAP were enrolled. Monotherapy was prescribed in 54.7% (n = 345) of the patients, and combination therapy was prescribed in 45.3% (n = 286). There was no significant difference in 30-day mortality between the two groups (16.8% vs. 18.2%, P = 0.729) or even after the PSM (17.5% vs. 18.2%, P = 0.913). After the PSM, adjusted hazard ratio for 30-day mortality from the combination therapy was 1.646 (95% confidence interval, 0.782–3.461; P = 0.189) in the Cox proportional hazards model. Moreover, there was no significant difference in the appropriateness of initial empiric antibiotics between the two groups (55.0% vs. 56.8%, P = 0.898). The proportion of multidrug-resistant (MDR) pathogens was high in both groups. Conclusion Empiric anti-pseudomonal fluoroquinolone combination therapy showed no survival benefit compared to β-lactam monotherapy in patients with HAP. Caution is needed regarding the routine combination of fluoroquinolones in the empiric treatment of HAP patients with a high risk of MDR.