It is well known that spontaneous non-aneurysmal subarachnoid hemorrhage (SAH), also known as sine materia SAH (smSAH), has usually a better course and prognosis than its aneurysmal counterpart (aSAH). This might depend on different inflammatory mechanisms initiated by bleeding events of different origins. The aim of the present study was to explore the systemic inflammatory response in spontaneous SAH, comparing aSAH and smSAH. We performed a prospective observational study over a consecutive series of patients with SAH. For these patients, we collected all clinical data and, furthermore, performed venous blood sampling over six time points to analyze blood cells. We further performed the analysis of lymphocytes and monocytes by means of flow cytometry to quantify common subtypes. Statistical analysis included a t-student test, Chi-square test, multivariate logistic regression, and ROC analysis. 48 patients were included: six (12.5%) with a diagnosis of spontaneous smSAH, and forty-two patients (87.5%) with aSAH. Significant differences on Day 0 were found for neutrophils and a systemic neuro-inflammatory index, namely, systemic inflammatory response index (SIRI). At the ROC analysis, neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and SIRI exhibited satisfactory predictive power on day 0. At the multivariable logistic regression analysis, the combined index (NLR, LMR, SIRI at day 0) yielded an OR of 0.59 (95% CI 0.29-1.21]). LMR at day 0 yielded an OR of 1.25 ([95% CI 0.94-1.68]), NLR at day 0 exhibited an OR of 0.68 ([95% CI 0.42-1.09]), and SIRI at day 0 displayed an OR of 0.31 ([95% CI 0.06-1.49]). This preliminary study indicated a possible role of some inflammatory indices that point out the importance of innate and adaptive immunity in the etiopathogenetic mechanisms. Drugs modulating these responses could eventually counteract or, at least, reduce secondary damage associated with SAH.