Background: There are two types of pembrolizumab-containing strategies for patients with non-small cell lung cancer (NSCLC) exhibiting a high expression level of programmed death-ligand 1 (PD-L1) (tumor proportion score [TPS] ≥50%): the early combination of pembrolizumab plus chemotherapy, and chemotherapy after pembrolizumab failure. Which strategy is superior, however, remains unclear. Comparing progression-free survival (PFS) or progression after the next therapy line (PFS2) in previous clinical trials has not allowed any conclusions regarding superiority to be made. Instead, the time to failure of strategy (TFS), which represents the time until disease exacerbation when the same number of drugs has been used, should be used to compare the two strategies. Methods: We consecutively reviewed the efficacy and safety of first-line, pembrolizumab-containing regimens administered between December 2017 and November 2020. We divided the patients who received pembrolizumab as a first-line treatment into two groups according to whether they received chemotherapy: a pembrolizumab plus chemotherapy group (combo group), and a pembrolizumab monotherapy group (mono group). TFS was defined as the PFS in the combo group and the PFS2 in the mono group. We used the propensity score matching (PSM) method to reduce the bias. Results: Of the 964 patients with advanced NSCLC who underwent first-line treatment, 126 with a PD-L1 TPS ≥50% were eligible for inclusion in this analysis (89 in mono group, 37 in combo group). PSM matched 36 people from each of the two groups. The median follow-up period was 16.2 months (range, 0.1-34.3 months). The patient backgrounds were similar. The overall response rate (ORR) of the combo group was higher than that of the mono group (69.4% vs. 50.0%). The median PFS (mPFS) in the combo group was longer (11.4 months vs. 6.0 months). However, the median TFS (mTFS) of the two groups was almost the same (11.4 months vs. 11.7 months). At the time of the analysis, the median overall survival had not been reached. The frequency of all immune-related serious adverse events (irSAE) was similar, however, that of all SAE and AE leading to treatment discontinuation were larger in the combo group. Conclusions: The ORR of the combo group was higher than that of the mono group; however, the TFS was similar. We suggest that pembrolizumab plus chemotherapy, which can increase toxicity, might be of value in patients, producing a clinically meaningful increase in the ORR.