R,S-Hydroxyphosphonoacetic acid (H3HPA) is an inexpensive multidentate organic ligand widely used for the preparation of organo-inorganic hybrid materials. There are reports of several crystal structures and the variability of the resulting frameworks is strikingly high, in contrast with the simplicity of the ligand. In an attempt to investigate and rationalize some salient structural features of the crystal structures, we have carried out a systematic high-throughput study of the reaction of H3HPA with Ca2+ in aqueous solutions (pH values ranging 1.0-7.5) at room temperature and hydrothermally at 180 °C. The tested synthetic conditions yielded five crystalline singlephase Ca-H3HPA hybrids: Ca3(O 3PCHOHCOO)2·14H2O (1), Ca(HO 3PCHOHCOO) · 3H2O (2), Ca5(O 3PCHOHCOO)2(HO3PCHOHCOO)2· 6H2O (3), CaLi(O3PCHOHCOO) (4), and Ca 2Na(O3PCHOHCOO)(HO3PCHOHCOO) · 1.5H 2O (5). Four new crystal structures, 2-5, are reported (three from powder diffraction data and one from single-crystal data), which allowed us to unravel some key common structural features. The Ca-H3HPA hybrids without an extra alkaline cation, 1-3, contain a common structural motif, which has been identified as a linear Ca-H3HPA-Ca-H3HPA-Ca trimer. This inorganic motif has a central Ca2+ in a distorted octahedral environment, whereas the two side Ca2+ cations are in an eight-coordinated oxygen-rich environment. The H3HPA ligands are chelating the central Ca2+ through two pairs of carboxylate and phosphonate oxygen atoms forming six-membered rings, Ca-O-C-C-P-O-Ca. This coordination mode allows the peripheral Ca(II) ions to bind the ligand through the-OH group and the other carboxylate oxygen, forming a fivemembered ring, Ca-O-C-C-O-Ca. The presence of alkaline cations, Li and Na+, disrupt this common structural feature leading to highly dense frameworks. Finally, similarities (and differences) between Ca-H3HPA and Cd-H 3HPA hybrids are also discussed.