Background: HHPG-19K (19K) is a long-acting pegylated recombinant G-CSF that can be dosed only once-per-chemo cycle. The aim of this phase III study was to investigate the efficacy/safety of HHPG-19K as prophylactic therapy in patients with advanced NSCLC treated with myelosuppressive chemotherapy. Methods: Patients were randomized (1:1:1) blindly to three treatment arms to receive 19K 100mg/kg, 6mg fixed dose or CONTROL (saline) in cycle 1. In cycles 2 to 4 following unblinding at the end of cycle 1, patients in CONTROL received short-acting G-CSF at dose of 5μg/kg once daily subcutaneously 48h after chemotherapy while patients randomized in 2 19K arms to receive the same doses as in cycle 1. All patients received 4 cycles of docetaxel (75mg/m²) plus cisplatin (75mg/m²) or carboplatin (AUC=5) per 21 days. The primary endpoint was the incidence of grade 3/4 neutropenia evaluated in cycle 1. Results: 151 chemo-naive patients with histopathology stage III/IV NSCLC enrolled into this study. The distribution of patients' baseline characteristics was well balanced among 3 arms. The incidence of grade 3/4 neutropenia was significantly decreased in patients received 19K 100µg/kg and 6mg-fixed compared to CONTROL in cycle 1 and showed no statistical difference in cycle 2 to 4. Mean duration of grade 3/4 neutropenia and median recovery time from neutropenia for two 19K arms were significantly shorter than that of CONTROL in cycle 1 and were similar in three arms in cycles 2 to 4. Four (8.00%) febrile neutropenia were observed in CONTROL in cycle 1 only. Nausea, fatigue and anorexia were the most common observed adverse events and no statistical difference among three arms in all cycles. Conclusions: This study demonstrated that the efficacy of HHPG-19K (either 100 µg/kg or 6 mg-fixed dose) was superior to placebo treatment and was comparable to short-acting G-CSF as prophylactic use in patients with NSCLC receiving chemotherapy. HHPG-19K was well tolerated and no unexpected adverse events were observed. The 6 mg-fixed dose is more convenient for administration and is recommended in further clinical practice. Clinical trial information: NCT01560195.