Objective: The present paper identifies and assesses the effect of critical factors on the risk of motorcycle loss-of-control (LOC) crashes. Method: Data come from a French project on road crashes, which comprises all fatal road crashes and a random sample of 1/20th of non-fatal crashes in France in 2011, based on police reports. A case-control study was carried out on a sample of 903 crashes for 444 LOC motorcycle riders (case) and 470 non-LOC and non-responsible motorcycle riders (control). The sample was weighted due to the randomization of non-fatal crashes. Missing values were imputed using multiple imputation. Results: Road alignment and surface conditions, human factors and motorcycle type played important roles in motorcycle LOC crashes. Riding in a curve was associated with a 3-fold greater risk of losing control of motorcycle than riding in a straight line. Poor road adhesion significantly increased the risk of losing control; the risk increased more than 20-fold when deteriorated road adhesion was encountered unexpectedly, due to loose gravel, ice, oil, bumps, road-marking, metal plates, etc. For motorcyclists, riding with a positive blood alcohol concentration (over or equal to the legal limit of 0.5g/l) was very dangerous, often resulting in losing control. The risk of LOC crash varied for different types of motorcycle: riders of roadsters and sports bikes were more likely to have a LOC crash than riders of basic or touring motorcycles. In addition, LOC risk increased with speed; a model using the square of the traveling speed showed better fit than one using speed itself. Conclusion: The LOC crash factors related to riders, vehicles and road infrastructure identified here were expected, but were rarely identified and taken simultaneously into account in previous studies. They could be targeted by countermeasures to improve motorcyclist safety.