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Background: In non-small cell lung cancer (NSCLC) patients off erlotinib therapy, positron emission tomography (PET) using [C]erlotinib distinguished epidermal growth factor receptor (EGFR) mutations from wild-type EGFR. However, tumor uptake of [C]erlotinib during erlotinib therapy is unknown. Therefore, the aims of this study were to evaluate tumor [C]erlotinib uptake in NSCLC patients both on and off erlotinib therapy, to evaluate the effect of erlotinib therapy on tumor perfusion and its correlation to tumor [C]erlotinib uptake, and also, to investigate simplified uptake parameters using arterial and venous blood samples. Methods: Ten patients were to be scanned twice with a 1-2-week interval, i.e., on (E+) and off (E−) erlotinib therapy. Each procedure consisted of a low-dose CT scan, a 10-min dynamic [O]HO PET scan, and a 60-min dynamic [C]erlotinib PET scan with arterial and venous sampling at six time points. In patients(E+), the optimal compartment model was analyzed using Akaike information criterion. In patients(E−), the uptake parameter was the volume of distribution ( V), estimated by using metabolite-corrected plasma input curves based on image-derived input functions and discrete arterial and venous blood samples. Tumor blood flow (TBF) was determined by rate constant of influx (K1) of [O]HO using the 1T2k model and correlated with V and K1 values of [C]erlotinib. The investigated simplified parameters were standardized uptake value (SUV) and tumor-to-blood ratio (TBR) at 40-60 min pi interval. Results: Of the 13 patients included, ten were scanned twice. In patients(E+), [C]erlotinib best fitted the 2T4k model with V. In all patients, tumor V(E+) was lower than V(E−) (median V(E−) = 1.61, range 0.77-3.01; median V(E+) = 1.17, range 0.53-1.74; P = 0.004). Using [O]HO, five patients were scanned twice. TBF did not change with erlotinib therapy, TBF showed a positive trend towards correlation with [C]erlotinib K1, but not with V. TBR and TBR, using both arterial and venous sampling, correlated with V(E−) (all r >0.9, P < 0.001), while SUV did not. In patients off and on therapy, venous TBR underestimated arterial TBR by 26 ± 12 and 9 ± 9 %, respectively. Conclusions: In patients on erlotinib in therapeutic dose, tumor V decreases with high variability, independent of tumor perfusion. For simplification of [C]erlotinib PET scanning protocols, both arterial and venous TBR 40-60 min post injection can be used; however, arterial and venous TBR values should not be interchanged as venous values underestimate arterial values. Trial registration: Registered at the Netherlands Trial Registry: . [ABSTRACT FROM AUTHOR]