Background: According to the Response Evaluation Criteria in Solid Tumors (RECIST), progressive disease (PD) is diagnosed under two conditions: an increase in size of pre-existing lesions (IS) and the appearance of new lesions (NL). We retrospectively investigated the difference in the prognosis between IS and NL.Methods: Patients receiving drug therapies for metastatic breast cancer between 2004 and 2015 at our institution were reviewed. The survival time after NL and IS was compared and the frequency of NL with each drug calculated.Results: For the 107 eligible patients, the survival time after NL at second-line chemotherapy was significantly worse than after IS (median survival time 4.3 months vs. 20.3 months, p = 0.0048). Maintenance therapy with bevacizumab or trastuzumab had a high frequency of NL (88.9%), and third-line eribulin had a low frequency of NL (16.7%). A multivariate analysis showed that NL at second-line chemotherapy was not an independent risk factor (hazard ratio 1.02, 95%; confidence interval 0.54-1.93, p = 0.95) for the total survival time.Conclusions: Patients with IS had a better survival after PD than those with NL. We may be able to avoid changing drug therapy for patients without NL and allow them to continue drug therapy for longer.