The Highway Safety Manual (HSM) provides an algorithm and associated knowledge to predict crashes on different types of facilities. This algorithm requires calibration to current local conditions through a procedure prescribed in the HSM to enhance its transferability. However, no procedure assesses the transferability. To fill this void, this paper focuses on a methodology to assess the transferability of the key HSM algorithm components—the baseline safety performance function and the crash modification factors (CMFs)—and uses the Italian road network as an illustrative case study. The calibration of the HSM crash prediction model is investigated with a data set for two-lane two-way rural highways to demonstrate some tools that could be used by jurisdictions around the world to assess the validity and compatibility of the CMFs and the base models, as well as the performance of the complete algorithm. A comparison with the results from a similar study carried out in Canada is provided to supplement the conclusions on the transferability of the HSM algorithm outside the United States.