Age-adjusted systolic blood pressure is higher in males than females. Genetic factors may account for this sex-specific variation. To localize sex-specific quantitative trait loci (QTL) influencing blood pressure, we conducted a genome scan of systolic blood pressure, in males and females, separately and combined, and tested for aggregate and QTL-specific genotype-by-sex interaction in American Indian participants of the Strong Heart Family Study. Blood pressure was measured 3 times and the average of the last 2 measures was used for analyses. Systolic blood pressure was adjusted for age and antihypertensive treatment within study center. We performed variance component linkage analysis in the full sample and stratified by sex among 1168 females and 726 males. Marker allele frequencies were derived using maximum likelihood estimates based on all individuals, and multipoint identity-by-descent sharing was estimated using Loki. We detected suggestive evidence of a QTL influencing systolic blood pressure on chromosome 17 at 129 cM between markers D17S784 and D17S928 (logarithm of odds [LOD] = 2.4). This signal substantially improved when accounting for QTL-specific genotype-by-sex interaction (P = 0.04), because we observed an LOD score of 3.3 for systolic blood pressure in women on chromosome 17 at 136 cM. The magnitude of the linkage signal on chromosome 17q25.3 was slightly attenuated when participants taking antihypertensive medications were excluded, although suggestive evidence for linkage was still identified (LOD = 2.8 in women). Accounting for interaction with sex improved our ability to detect QTLs and demonstrated the importance of considering genotype-by-sex interaction in our search for blood pressure genes.