Weight gain in women receiving chemotherapy for breast cancer is associated with a higher risk of recurrence. Using metabonomic profiling, we recently reported that plasma lactate and alanine were prognostic for weight gain in individuals with breast cancer receiving chemotherapy. The role of lipid second messengers has not been studied. We assessed serum levels of sphingosine-1-phosphate (S1P), a known secreted lipid second messenger with a role in cell growth, in sequential samples from post-menopausal women receiving standard chemotherapy for early breast cancer and correlated these with body mass measurements and metabonomic profiling. While serum S1P levels prior to treatment did not correlate with body weight changes or circulating alanine and lactate, S1P levels measured during therapy were inversely correlated with weight gain (P = 0.04), but not weight loss (P = 0.74) or no change in weight (P = 0.5), suggesting a role of dynamic circulating S1P in adipocyte growth. These data provide evidence for an association between serum S1P and weight gain during chemotherapy cycles in women with breast cancer. Lipid second messengers have a role in chemotherapy-induced weight gain in breast cancer.