<p>This study aimed to investigate and compare the ionomic profiles of vitreous humor and serum in patients with rhegmatogenous retinal detachment (RD) to identify potential ionic biomarkers associated with the disease.Vitreous humor and serum samples were collected from five patients with RD and five patients with macular hole (MH) serving as controls. Inductively coupled plasma mass spectrometry (ICP-MS) was employed for the qualitative and quantitative analysis of multiple ions. Multivariate statistical analyses, including principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA), were applied to evaluate intergroup differences. Ionomics analysis showed that there was a significant difference in the vitreous humor ion spectrum between the RD group and the MH group, but there was no difference in the serum ion spectrum between the two groups, except zirconium ions (Zr). 34 differential ions were identified in the vitreous humor, of which 28 were up-regulated (including Zr, As, Cs, Cu and Cd) and 6 were down-regulated (including Na, K, Mn, B and Ni) in the RD group. The Zr ion levels in the vitreous humor and serum of RD patients were significantly higher than those of the MH control group (<i>p</i> &lt; 0.05). The two groups can be clearly distinguished according to the vitreous humor ion spectrum, while the serum ion spectra of the two groups are highly overlapping. The study identifies a significant increase in zirconium ion levels in the vitreous humor and serum of RD patients. These findings suggest that zirconium ions may be associated with the pathogenesis of RD and could serve as a novel, minimally invasive biomarker for early screening and risk assessment of the condition.</p>