Capsaicin is the active substance responsible for the pungent sensation produced by red pepper. In order to approach the underlying genetic mechanism for preference of red pepper, we conducted a 12-h, 1-bottle intake test of capsaicin solution using both male and female animals from the Mishima battery of mouse strains: 10 wild-derived inbred strains (PGN2, BFM/2, HMI, CAST/Ei, NJL, BLG2, CHD, SWN, KJR, MSM), 1 strain derived from the so-called fancy mouse (JF1), and 3 widely used laboratory strains (C57BL/6J, DBA/1J and BALB/cAnN). The concentration of capsaicin was increased from 0.5 to 15 μM successively. Gender differences were not observed in this test, but we found striking strain differences in capsaicin intake. Relative to baseline water intake, C57BL/6J and DBA/1J consumed 10%, whereas two wild strains, KJR and MSM, ingested approximately 60% of the 15-μM capsaicin solution. In a 2-bottle fluid preference test, both C57BL/6J and MSM strains reject capsaicin fluid even at the 0.5-μM concentration, which indicates that the receptors for capsaicin in these strains recognize capsaicin at a similar level. Thus, the strain differences at higher capsaicin concentrations in the 1-bottle test may reflect differences in central nervous system response to the capsaicin solution. The genetic difference in intake of capsaicin observed in these strains may provide a useful tool for identifying genes underlying response to red pepper in mice and other mammalian species.