Many kinds of small heat shock proteins (sHSPs) are able to prevent protein aggregation in stress, which show the ATP independent chaperone-like activity. The smallest protein HSP12.1 in sHSP family of the nematode Caenorhabditis elegans exhibits chaperone-like activities in vitro. It prevents protein aggregation in a certain extent when use insulin, ADH and lysozyme as the substrates, though it is not as efficient as the typical chaperones (such as HSP16.1 in C. elegans). By contrast, the other three sHSP12s (HSP12.2, HSP12.3 and HSP12.6), which have similar molecular masses and primary structure, appear devoid of in vitro chaperone-like activities. In addition, overexpressing HSP12.1 enhances cell thermotolerance of Escherichia coli. The survival rate of the HSP12.1 overexpressed cells is 4-fold higher than the control, yet whether it does the same function in C. elegans is still unknown. Results indicate that C-terminal region is not necessary for the chaperone-like activity of sHSPs, for HSP12.1 terminates a short C-terminal tail. N-terminal domain may play a relatively important role in the exhibition of chaperone-like activities, while α-crystalline domain may also involve in this function.