Background: Suicidal ideation (SI) represents a clinical challenge in patients with treat-ment-resistant depression (TRD), and the management of this condition would be as rap-id and effective as possible. Intranasal Esketamine has shown promise in patients with TRD due to its rapid onset of action on both SI and depressive symptoms. Since this med-ication has been recently approved, real-world data on its efficacy remains scarce, and lit-tle is known about which patients are most likely to benefit from this approach. Aims: This study aimed 1) to evaluate the efficacy of intranasal Esketamine on SI and depressive symptoms and 2) to find potential predictors of clinical response. Methods: Patients with TRD who received intranasal Esketamine were included in the study. Clinical evaluations and psychometric assessments were made at baseline (T0) and at five subsequent time points (one week [T1], one month [T2], two months [T3], three months [T4], and six months [T5]). SI was assessed using the Columbia Suicide Severity Rating Scale (C-SSRS), and depressive symptoms were evaluated using the Montgomery–Åsberg Depression Rating Scale (MADRS). Furthermore, socio-demographic, clinical, and pharmacological data were collected. Results: Eighty patients diagnosed with TRD were enrolled. Suicidal ideation (C-SSRS items 1–5) decreased from 1.56 ± 1.65 at baseline to 0.78 ± 1.28 at T1 and 0.12 ± 0.52 at T5 (all p < .001). MADRS fell from 31.81 ± 7.94 to 23.62 ± 9.08 and 10.19 ± 7.33 at the same time points (all p < .001). By T1, 68.4% achieved SI response on the C-SSRS. MADRS response rate increased from 16.7% at T1 to an overall response of 62.5% at T5. Male sex predicted lower odds of early response on the C-SSRS (OR = 0.21, p = .031); no other baseline variable was significant as a predictor. Conclusions: Intranasal Esketa-mine has been shown to be effective in the rapid reduction and lysis of SI in patients with TRD. Male gender was found as a negative predictor of response, suggesting the im-portance of considering gender differences during treatment planning.