Objectives/Hypothesis: Despite its negative impact on cancer patients, there are few animal models of cancer cachexia. Our hypothesis was that different human cell lines would variably induce cachexia.

Study Design: Prospective animal study.

Methods: We established two xenograft models in athymic mice and compared these with a cachexigenic cell line, the murine adenocarcinoma 16 (MAC16) cell line. Eight‐week‐old female, athymic mice were injected with human head and neck cell lines (JHU022, JHU012) and the MAC16 cell line. Body weight, food intake, body composition, leg weights, serum cytokines, and lipid mobilizing factor (LMF) were compared.

Results: Mean food intake for all groups was equivalent. Mean percent change in body weight after 18 days was 18%, 19%, 12%, and 3% for control, JHU012, JHU022, and MAC16 experimental groups, respectively. Both JHU022‐ and MAC16‐injected mice showed wasting even when tumor burden was low. In contrast, mice injected with JHU012 developed larger tumors yet lacked evidence of cachexia. These mice demonstrated loss of lean body mass but not fat mass. Serum cytokine levels for interleukin (IL)‐1α and IL‐1β were elevated in JHU022‐bearing mice, whereas IL‐1α, IL‐6, interferon (IFN)‐γ, and tumor necrosis factor alpha (TNF)‐α were elevated in MAC16‐bearing mice. LMF was present in both the JHU022 and JHU012 cell lines.

Conclusions: The JHU022 cell line caused more severe cachexia than the JHU012 cells, suggesting these cell lines may be used to further study cancer cachexia. IL‐1α and IL‐1β in the JHU022 model may be mediators of cachexia, whereas TNF‐α, IFN‐γ, and IL‐6 may be mediators in MAC16‐induced cachexia.