Fragment 450–650 of the spike (S) protein (S450–650) of severe acute respiratory syndrome‐associated coronavirus (SARS‐CoV) contains epitopes capable of being recognized by convalescent sera of SARS patients. Vaccination of mice with recombinant S450–650 (rS450–650) can induce Abs against SARS‐CoV, although the titer is relatively low. In the present study, a fusion protein linking a fragment (residues 39–272) of murine calreticulin (CRT) to S450–650 in a prokaryotic expression system was created. Compared with target antigen alone, the recombinant fusion product (rS450–650‐CRT) has much improved hydrophilicity and immunogenicity. The S450–650‐specific IgG Abs of BALB/c mice subcutaneously immunized with rS450–650‐CRT were in substantially higher titer (approximately fivefold more). Furthermore, the fusion protein, but not rS450–650 alone, was able to elicit S450–650‐specific IgG responses in T cell deficient nude mice. Given that rCRT/39–272 can drive the maturation of bone‐marrow‐derived dendritic cells, directly activate macrophages and B cells, and also elicit helper T cell responses in vivo, we propose that fragment 39–272 of CRT is an effective molecular adjuvant capable of enhancing target Ag‐specific humoral responses in both a T cell‐dependent and independent manner. Fusion protein rS450–650‐CRT is a potential candidate vaccine against SARS‐CoV infection.