Weak nonbonded interactions between a divalent sulfur (S) atom and a main-chain carbonyl oxygen (O) atom have recently been characterized in proteins. However, they have shown distinctly different directional propensities around the O atom from the S...O interactions in small organic compounds, although the linearity of the C-S...O or S-S...O atomic alignment was commonly observed. To elucidate the observed discrepancy, a comprehensive search for nonbonded S...O interactions in the Cambridge Structural Database (CSD) and MP2 calculations on the model complexes between dimethyl disulfide (CH3-SSCH3) and various carbonyl compounds were performed. It was found that the O atom showed a strong intrinsic tendency to approach the S atom from the backside of the S-C or S-S bond (in the sigma(S)* direction). On the other hand, the S atom had both possibilities of approach to the carbonyl O atom within the same plane (in the no direction) and out of the plane (in the To direction). In the case of S...O(amide) interactions, the pi(O) direction was significantly preferred as observed in proteins. Thus, structural features of S...O interactions depend on the type of carbonyl groups involved. The results suggested that S...O interactions may control protein structures to some extent and that the unique directional properties of S...O interactions could be applied to molecular design.