Abstract: Odontocete depredation on longlines involves socioeconomic and conservation issues with significant losses for fisheries and potential impacts on wild populations of depredating species. As technical solutions to this conflict are limited and difficult to implement, this study aimed to identify fishing practices that could reduce odontocete depredation, with a focus on killer whales (Orcinus orca) interacting with Patagonian toothfish (Dissostichus eleginoides) longliners off the Crozet islands. Data collected by fishery observers from 6013 longline sets between 2003 and 2013 allowed us to statistically detect the significant influence of five operational variables using GLMMs. The probability of interactions between vessels and killer whales was decreased by (i) the number of vessels operating simultaneously in the area: the limited number of depredating killer whales may induce a dilution effect with increased fleet size, and (ii) depth of longline sets: vessels operating in shallow waters may be more accessible to whales that are initially distributed on peri-insular shelves. The cpue was negatively influenced by (iii) length of longlines: longer sets may provide killer whales access to a greater proportion of hooked fish per set, and positively influenced by (iv) hauling speed: increased speed may shorten the time during which toothfish are accessible to whales during hauling. The time it takes for killer whales to reach vessels was positively correlated to (v) the distance travelled between longline sets with an estimated threshold of 100 km beyond which whales seem to temporarily lose track of vessels. These findings provide insightful guidelines about what fishing strategy to adopt given these variables to reduce killer whale depredation here and in similar situations elsewhere. To a greater extent, this study is illustrative of how collaborative work with fishermen in a fully controlled fishery framework may lead to the definition of cost-limited and easy-to-implement mitigation solutions when facing such human-wildlife conflict.