Background <p>Combination therapy is the standard treatment for curatively unresectable gastric cancer; however, its effectiveness in patients aged ≥ 75&#xa0;years remains unclear. This study investigated the effectiveness of combination therapy in enhancing overall survival.</p> Methods <p>We retrospectively analyzed nationwide medical claims data for patients with unresectable advanced gastric cancer who received chemotherapy between October 2010 and May 2023. Overall survival and real-world progression-free survival were the primary and secondary outcomes, respectively. Patient characteristics were adjusted using inverse probability of treatment weighting, and inverse probability of treatment weighting-adjusted hazard ratios were calculated.</p> Results <p>Among 6213 patients (mean age 80.0&#xa0;years, 70.3% men), 4988 received monotherapy and 1225 received combination therapy. The median (interquartile range) number of first-line therapy cycles and duration of first-line therapy were three cycles and 4.4 (2.1–7.9) months for monotherapy and four cycles and 5.3 (2.7–9.1) months for combination therapy, respectively. The median overall survival was 9.7 and 11.3&#xa0;months (significant adjusted hazard ratio) while real-world progression-free survival was 4.4 and 5.1&#xa0;months (significant adjusted hazard ratio) for monotherapy and combination therapy, respectively. In multivariate analysis, the adjusted hazard ratio for overall survival was not significant.</p> Conclusions <p>After adjusting for background factors, compared with monotherapy, combination therapy did not extend overall survival; however, an extension of real-world progression-free survival was observed. These results suggest that combination therapy is an effective treatment option for older patients with unresectable gastric cancer. Further studies considering the systemic condition of older patients are necessary.</p>