Background Histiocytic sarcoma (HS) is a rare but aggressive malignancy in humans that is poorly responsive to existing treatments. Although rare in most breeds of dogs, HS is common in Bernese mountain dogs (BMDs). Objective Determine risk factors associated with development of HS in BMD. Animals A total of 216 BMD were registered with the Berner‐Garde Foundation. Methods An internet‐based cross‐sectional survey was used to collect information from owners of BMD diagnosed with HS and owners of disease‐free littermates of dogs with HS. Mixed‐effects logistic regression (MELR) and conditional logistic regression (CLR) were used in parallel to examine associations between potential risk factors and the occurrence of HS. Results When controlling for litter as a marker of relatedness, dogs diagnosed with orthopedic conditions were found to be more likely to develop HS (MELR, OR: 2.5, 95% CI: 1.5, 5.2; CLR, OR: 2.81, 95% CI: 1.1, 7.3), whereas dogs receiving prescription anti‐inflammatory medications were found to be at considerably lower risk of developing HS (MELR, OR: 0.42, 95% CI: 0.2, 0.8; CLR, OR: 0.32, 95% CI: 0.1, 0.8). Conclusions and Clinical Importance These results suggest inflammation may be a modifiable risk factor for the development of HS in BMD.