The article presented the issue of securing semi-trailer trucks and trailers during their transport using intermodal railway wagons as a part of combined transport. This issue was analysed in different operational conditions related to loading level, cross-winds influence, inertia forces due to the emergency braking, and track curvature. According to general rules of loading and securing cargo, described in the internal and UIC regulations, the transported load should be positioned and secured with minimised risk of undesirable displacement or rolling over during transport. Basic analysis showed that adverse conditions such as strong winds or emergency braking may require adequate additional cargo protection. The lack thereof may result in a severe accident or damage to the transported vehicle or the nearby structures. The presented results for generic road and railway freight vehicles showed that the required anti-rollover torque for a semi-trailer mounted on the railway wagon platform may differ considerably (almost four times at the same maximum tested airflow speed) depending on the conditions related to aerodynamic and inertia influence. The potential weaknesses of the analysis relate to the impracticality of experimental tests for roll-over (or derailment) events under high levels of cross-wind, due to economic and safety reasons. The analysis can be extended in the future by including unsteady aerodynamic forces and a full-vehicle model based on the multi-body method for a specific design solution.