Histiocytic sarcoma (HS) is an aggressive malignant tumor of histiocytes, which can affect almost any organ in the body and is characterized by a broad array of tumor locations and clinical presentations. So far, no complete overview exists of the array of clinical aspects of HS in specific dog breeds in large groups. Therefore, we investigated the clinical characteristics of HS in a population of Bernese Mountain Dogs (BMD; n = 365) and Flat-Coated Retrievers (FCR; n = 289), which are two of the most affected dog breeds. Cases were selected from databases from different pathology services, and clinical information was retrospectively collected for each case. Localized HS was reported significantly more frequently in the FCR (60.6%) than in the BMD (39.2%), and disseminated HS was recorded significantly more frequently in the BMD (60.8%) than in the FCR (39.4%). Lameness was seen more often in FCR than in BMD, and the vast majority (78.1%) of LHS leading to lameness was located in the front legs in the FCR, while in the BMD, there was a more even distribution. BMD had significantly more often leukocytosis and thrombocytopenia, even corrected for the type of HS, than FCR. No significant difference in the frequency of anemia was recorded between BMD and FCR. In those dogs in which blood examination was performed, hypercalcemia was diagnosed in 15 BMD, while none of the FCR had hypercalcemia. The new information provided in this study can aid the diagnostic process and allow for prompt treatment recommendations.