The aim of this multicenter retrospective study was to evaluate the incidence of hyperprogressive disease after treatment with pembrolizumab as a second-line treatment in patients (n=167) with non-small-cell lung cancer (NSCLC) with metastatic disease whose tumors expressed programmed death-ligand-1 in ≥1% and to search for factors associated with its development. All patients received platinum-containing chemotherapy as a first-line treatment. The neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and their derivations were retrospectively analyzed. The psoas major muscle area (PMMA) was calculated at the L3 position on computed tomography before chemotherapy and immunotherapy. Patients with ∆PMMA≥10% were considered to have sarcopenia (low muscle mass). We also performed multinomial logistic regression to estimate the effects of hematological biomarkers and ∆PMMA on the response to immunotherapy. Hyperprogressors (HPs) had significantly higher NLRs, PLRs and ∆PMMA levels than the other patients. Moreover, in multivariate regression analysis, higher levels of ∆PMMA were associated with a decreased likelihood of being a progressor (P) (OR, 0.81; 95% CI, 0.65-0.99; p=0.047) or a nonprogressor (NP) (OR, 0.76; 95% CI, 0.62-0.94; p=0.012) vs an HP. In multivariate analysis, higher NLRs tended to decrease the likelihood of being a P vs an HP (OR, 0.66; 95% CI, 0.42-1.06; p=0.09) and significantly decrease the likelihood of being an NP vs an HP (OR, 0.44; 95% CI, 0.28-0.69; p<0.0001). Our data suggest that a high pre-immunotherapy NLR and the presence of sarcopenia are potential risk factors for the development of hyperprogressive disease.