We prospectively evaluated the utility of ESR1 and PIK3CA mutation analysis with cell-free DNA (cfDNA) using droplet digital PCR (ddPCR) for the efficacy of endocrine therapy (ET) in hormone receptive positive (HR+) metastatic breast cancer (MBC) patients. CfDNA was analyzed just before the start of ET for MBC. E380Q, Y537N, Y537S, and D538G were assessed for ESR1 mutations and H1047R, E545K, and E542K were assessed for PIK3CA mutations. A total of 75 patients were enrolled. Of those, 31 (41.3%) received letrozole with palbociclib, and 28 (37.3%) received exemestane and everolimus (EverX). ESR1 mutations were found in 36 (48.0%) patients, of which 16 (21.3%) had more than one variant. Seventeen (23.6%) patients had one PIK3CA mutation and 8 (11.1%) had two. In the total population, time to progression of the first ET after enrollment (TTP1) decreased significantly as the number of ESR1 mutations increased (p < 0.001). PIK3CA mutations were also significantly associated with shorter TTP1 (median TTP1: 16.2 months vs. 10.9 months, p = 0.03). In contrast, PIK3CA mutations were significantly associated with longer TTP in patients receiving EverX treatment (median TTP of EverX: 15.9 months vs. 5.2 months, p = 0.01) and remained a significant factor in multivariable analysis for TTP of EverX in this subgroup (hazard ratio = 0.2, 95% CI = 0.1- 0.8, p = 0.03). ESR1 and PIK3CA mutations in cfDNA were associated with clinical efficacies of ET in HR+ MBC patients.