Heat stroke is a life-threatening illness characterized by an elevated core body temperature. Despite adequate lowering of the body temperature and support treatment of multiple organ-system function, heat stroke is often fatal. 3-(5'-Hydoxymethyl-2'-furyl)-1-benzyl-indazol (YC-1) been identified as an activator of soluble guanylate cyclase. To evaluate whether YC-1 protects multiple organ dysfunctions and improves survival during heat stroke and its mechanism. Male Sprague-Dawley rats untreated or treated with either YC-1 or quercetin (heat shock protein (Hsp) 70 inhibitor) were exposures to heat as a model of heat stroke. The mean arterial pressure (MAP), heart rate, rectal temperature (Tco), survival time, and plasma biochemical data, intracellular Hsp70 and heat shock factor-1 expression were measured. The value of MAP, heart rate and Tco of untreated heat stroke (HS) group were all significantly lower than that of normothermal (NT) group. Biochemical markers evidenced that liver and kidney injuries of HS group were significantly higher than that of NT groups. YC-1 (20mg/kg) pretreatment with heat stroke (YC-1+HS) group, the MAP and heart rate were return to normal, and the biochemical markers were all significantly recovered to normal. The survival time of HS group, NT group and YC-1+HS group were 21, 480, and 445 min, respectively. The expression of Hsp70 and HSF-1 in liver and renal of YC-1+HS group was significantly higher than that of HS group. All of the protective effects of YC-1 were all significantly suppressed when pretreated with quercetin (400mg/kg). Results indicate that YC-1 may improve survival due to induce Hsp70 overexpression.