Background: Due to the severe toxicity of carboplatin and cisplatin, nedaplatin and lobaplatin are increasingly used in advanced lung adenocarcinoma (LUAD). However, there are no studies comparing lobaplatin with nedaplatin in the treatment of advanced LUAD. In this study, patients with LUAD were treated with PN or PL, and the safety and efficacy of the two regimens were evaluated. Methods: A total of 344 locally advanced or advanced LUAD patients first-line treated with nedaplatin plus pemetrexed (PN) or lobaplatin plus pemetrexed (PL) were enrolled. There were 175 patients in PN group and 169 patients in PL group. The primary endpoint was leukopenia and thrombocytopenia (grade 3 and 4). Secondary endpoints included disease control rate (DCR), objective response rate (OCR), and progression-free survival (PFS). Results: In PN group, the incidence of myelosuppression among 3/4 grade adverse events were 7.4%, and 18.3% in the group that received PL (P < 0.01). Incidences of thrombocytopenia in PN group were 2.3% and in PL group were 10.1% (P < 0.01). The overall PFS of the PN group was 5.6 months (95% CI, 3.76-7.44) and PL group was 4.9 months (95% CI, 4.04-5.76) (P = 0.035). In mutation-negative patients, the median PFS was 5.0 months (95% CI, 3.84-6.17) in the PN group and 4.8 months (95% CI, 4.03-5.57) in the PL group (P = 0.05). There was no significant difference in DCR and ORR between the two groups (P > 0.05). Conclusions: The PL group is associated with a higher risk of hematologic toxicity than PN group. The PFS of PN group was better than that of PL group.