Purpose Immune checkpoint inhibitors (ICIs) have improved the prognosis of cancer patients significantly with few predictive makers for treatment efficiency. Since interferon-gamma (IFN-gamma) displayed its association with immunotherapy, we explored the correlation between IFN-gamma and the efficacy of ICIs in tumor treatment. Methods We retrospectively examined cancer patients who received immune checkpoint inhibitors as first-line therapy at the Fourth Hospital of Hebei Medical University. The patients were divided into a low concentration group of IFN-gamma (<= 1.2 pg/mL) and a high concentration group (>= 1.3 pg/mL) to evaluate the efficacy, which was indicated by the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Results Thirty-five patients with low IFN-gamma and 56 patients with high IFN-gamma were involved in the evaluation, and the DCR was significantly different between these two groups (p = 0.009) with a high group of 81.4% (95% CI 69-94%) and a low group of 51.9% (95% CI 32-72%). The subsequent Kaplan-Meier survival analysis showed that the high IFN-gamma patients displayed longer median OS than that of the low IFN-gamma patients (p = 0.049), while no statistical difference existed for PFS (p = 0.971). The multivariate analysis also confirmed that the high IFN-gamma level was independently associated with a better prognosis (HR: 0.318 95% CI 0.113-0.894, p = 0.030). Conclusions Basal serum IFN-gamma levels were associated with the DCR and OS of cancer patients with higher IFN-gamma exhibiting beneficial efficiency for ICIs treatment.