Background: Cancer patients frequently suffer from weight loss and systemic inflammation in the context of advanced disease, which is related to adverse outcome. Insulin-like growth factor (IGF)-I is an anabolic molecule implicated in the maintenance of muscle mass and cancer growth. We investigated potential correlations of IGF-I with an inflammatory and weight loss status and with clinical outcome. Methods: Baseline IGF-I plasma levels were measured in 77 patients (66 males, median age 65.5 ± 10.6 years), diagnosed with metastatic non-small cell lung cancer, and were correlated with serum albumin and C-reactive protein (CRP) levels, weight loss history, treatment response and overall survival. Results: IGF-I correlated with age (p = 0.01), histologic subtype (p = 0.019), albumin (p < 0.001) and CRP (p < 0.001). In univariate analysis, gender (p = 0.005), smoking status (p = 0.012), albumin (p = 0.034) and IGF-I (p = 0.017) were related to time to progression, while IGF-I (p = 0.003), gender (p = 0.049) and smoking status (p = 0.003) retained their significance in multivariate analysis. Age (p = 0.005), gender (p = 0.029), weight loss (p = 0.009), performance status (p < 0.001), number of metastatic sites (p = 0.004), albumin (p = 0.008), CRP (p = 0.022) and IGF-I (p = 0.042) were associated with overall survival, although only gender (p = 0.013), weight loss (p = 0.027), performance status (p = 0.015) and number of metastatic sites (p = 0.021) emerged as independent prognostic factors. Conclusion: IGF-I correlates with systemic inflammation and seems to play an independent predictive role in metastatic non-small cell lung cancer.