The methodological approach to safety evaluation of two-lane rural highway segments that is presented uses both analytical procedures referring to alignment design consistency models and safety inspection processes. A safety index (SI) that quantitatively measures the relative safety performance of a road segment is calculated from the procedure. The SI is formulated by combining three components of risk: the exposure of road users to road hazards, the probability of a vehicle's being involved in an accident, and the resulting consequences should an accident occur. This systematic and replicable procedure integrates two different, complementary approaches–one based on design consistency evaluations and the other on safety inspections–and makes it possible to address a wide variety of safety issues effectively. A further advantage of the procedure is its applicability on highways where crash data are either not available or unreliable. Validation of the procedure was carried out on a sample of roads by a comparison of the risk rank obtained by using the SI and accident history. The SI was assessed in 30 segments chosen from a sample of two-lane rural highways in Italy, and the actual accident situation was obtained with the empirical Bayes (EB) procedure. Spearman's rank correlation was used to determine the level of agreement between the rankings obtained with the two techniques. The results from the Spearman's rank-correlation analysis validate the SI, indicating that the ranking from the SI scores and the EB estimates agrees at the 99.9% level of significance with a correlation coefficient of 0.87.