<p>Selective recognition of SO₄²⁻ from HPO₄²⁻-containing environments is highly challenging, as SO₄²⁻ and HPO₄²⁻ not only share similar structures and sizes, but also exhibit similarities in many characteristics such as charge density, acidity, and hydration energy. In this contribution, a post-modifiable trapezoidal cage (<b>1a</b>) was developed to address the selective recognition of SO₄²⁻ from HPO₄²⁻, as well as to cope with the difficulties of trapezoidal cages in post-modification and property variation. Coupled with the newly explored [4 + 4] cyclization strategy, the synthesis efficiency of producing trapezoidal cages has also been greatly improved. Afterward, by taking advantage of the tetrahedrally deployed binding sites of the trapezoidal cage <b>1a</b>, selective recognition of SO₄²⁻ from HPO₄²⁻ can be realized even in complex environments containing many other anions. Through NMR, fluorescence, nonlinear fitting analysis, and HRMS experiments, the binding affinity and binding stoichiometry of <b>1a</b> + anion were extensively studied. The results demonstrate that <b>1a</b> + SO₄²⁻ follows a 1:1 host–guest binding mode and exhibits a much higher binding affinity (<i>K</i> ~ 1.7 × 10⁸&#xa0;M⁻¹) than HPO₄²⁻ (<i>K</i> = 2.6 × 10⁶&#xa0;M⁻¹) or any other anions (<i>K</i> = 10⁴–10⁵&#xa0;M⁻¹) in 5% methanol/chloroform. The selective recognition of SO₄²⁻ in complex environments including HPO₄²⁻ can provide valuable considerations for the precise design of receptors that can distinguish subtle structural differences in substrates, while the post-modification strategy may also help improve the synthesis and extendibility of other covalent cages.</p> Graphical abstract <p></p>