Recent animal studies showed that tumor-derived PTHrP induced cancer cachexia by fat browning with increased energy expenditure; however, clinical evidence from human data is insufficient.We investigated whether serum PTHrP levels independently predicts weight loss (WL) in cancer patients.From a longitudinal observational cohort, body mass index (BMI) of patients with measured serum PTHrP levels (n = 624) was assessed (median follow-up of 327 d).Cox hazard models were used to examine the predictive value of PTHrP for WL defined by consensus definition (WL [consensus], percentage WL < -5% or percentage WL < -2% plus BMI < 20 kg/m(2)) and by BMI-adjusted grades (WL [BMI adjusted]).The overall risk of WL (consensus) was 34.4%. Compared with PTHrP-negative subjects, patients with higher PTHrP levels (PTHrP ≥ median 5.7 pmol/L) had more WL (percentage WL, -6.9% vs -1.1%, P = .010) at follow-up. A higher PTHrP level was associated with an increased loss of body weight (β = -2.73), muscle (β = -1.85), and fat (β = -2.52) after controlling for age, sex, and BMI. Kaplan-Meier analysis demonstrated that subjects with higher PTHrP had increased WL risk compared with lower PTHrP or PTHrP-negative groups (52.0% vs 38.9% vs 29.7%, P < .001). Serum PTHrP was independently associated with an increased WL risk (hazard ratio [HR]1.23, P = .005) adjusted for potent predictors including serum levels of calcium, C-reactive protein, albumin, cancer stage, and performance status of patients. Consistent results were observed when BMI-adjusted WL was applied.Serum PTHrP levels predicted cancer-associated WL independent of the presence of hypercalcemia, inflammation, tumor burden, and other comorbidities.