The hydrophobic effect is a major driving force in all chemical and biological events involving chain collapse in aqueous solution. Here, we show that the burial of nonpolar solvent-accessible surface area (NSASA) is a powerful criterion to predict the folding and misfolding behavior of small single-domain proteins as a function of chain elongation. This bears fundamental implications for co- and post-translational protein folding in the cell and for understanding the interplay between noncovalent interactions and formation of native-like structure and topology. Comparison between the fraction of NSASA in fully unfolded and folded elongating chains shows that efficient burial of nonpolar surface area is preferentially achieved only when the polypeptide chain is almost complete. This effect has no preferential vectorial character in that it is present upon elongation from both the N and C termini. For incomplete chains that do not have the ability to fold and bury nonpolar surface intramolecularly, the overall hydrophobic nature of the polypeptide chain (expressed as FBA, i.e., fractional buried surface area per residue) dictates the tendency toward misfolding and self-association. N-terminal chains characterized by FBA exceeding 0.73 are likely to misfold and aggregate, if unable to fold intramolecularly.