Heterocyclic compounds have a prominent role in medicinal chemistry and drug design. They are not only useful as medicinally active compounds but also as a modular structural scaffold for drug design. Therefore, heterocycles are present in many ligands that exhibit a broad spectrum of biological activities. Pyazolopyrimidines are nitrogen heterocycles and are part of many biologically active compounds and marketed drugs. This study examines the non-covalent interactions between the pyrazolopyrimidine rings and receptor proteins through data mining and analysis of high-resolution crystal structures deposited in the Protein Data Bank. The Protein Data Bank contains 471 crystal structures with pyrazolopyrimidine derivatives as ligands, among which 50% contains 1H-pyrazolo[3,4-d]pyrimidines (Pyp1), while 38% contains pyrazolo[1,5-a] pyrimidines (Pyp2). 1H-Pyrazolo[4,3-d]pyrimidines (Pyp3) are found in 11% of the structures, and no structural data is available for pyrazolo[1,5-c]pyrimidine isomers (Pyp4). Among receptor proteins, transferases are found in most examples (67.5%), followed by hydrolases (13.4%) and oxidoreductases (8.9%). Detailed analysis of structures to identify the most prevalent interactions of pyrazolopyrimidines with proteins shows that aromatic π···π interactions are present in ∼91% of the structures and hydrogen bonds/other polar contacts are present in ∼73% of the structures. The centroid-centroid distances (dcent) between the pyrazolopyrimidine rings and aromatic side chains of the proteins have been retrieved from crystal structures recorded at a high resolution (data resolution <2.0 Å). The average value of dcent in pyrazolopyrimidine-protein complexes is 5.32 Å. The information on the geometric parameters of aromatic interactions between the core pyrazolopyrimidine ring and the protein would be helpful in future in silico modeling studies on pyrazolopyrimidine-receptor complexes.