This article examines the relationship between travel speeds and crashes on two-lane highways, accounting for traffic exposure and road infrastructure characteristics. The study's database included 179 road sections in Israel, which included free-flow travel speeds, 3-year injury crash data, traffic volumes, and road infrastructure characteristics. Preliminary analyses of in-data correlations supported the selection of appropriate speed and infrastructure indicators. Homogeneous groups of road sections were identified according to their characteristics. Negative binomial statistical models were fitted to injury crash counts for day and night hours, using speed indicators, section length, traffic volume, and the homogeneous road groups, which reflected various road design conditions. The models demonstrated a positive relation between mean speeds and crashes, while controlling for traffic and road characteristics. The expected crash change following higher travel speeds was more substantial for night hours. In line with previous research, section length, traffic volume, and worse road design were positively related to crashes.