Carbonyl-carbonyl (CO⋯CO) interactions are emerging noncovalent interactions found in many small molecules, polyesters, peptides and proteins. However, little is known about the effect of the relative orientation of the two carbonyl groups on the nature of these interactions. Herein, we first show that simple homodimers of acetone and formaldehyde can serve as models to understand the effect of relative orientations of the two carbonyl groups on the nature of CO⋯CO interactions. Further, from a comprehensive statistical analysis of molecules having inter- or intramolecular CO⋯CO interactions, we show that the molecules can be broadly categorized into six different structural motifs (I-VI). The analysis of pyramidality of the acceptor carbon atoms in these motifs and natural bond orbital (NBO) analysis suggest that the relative orientation of the two interacting carbonyl groups determines whether the orbital interaction between the two carbonyl groups would be n → π∗ or π → π∗ or a combination of both. © 2019 The Royal Society of Chemistry.