In this study we examined the clinical characteristics of relapse before and after complete clinical response (CR) to anthracycline-based combination chemotherapy in metastatic breast cancer (MBC). Our goal was to determine whether similar clinical trends could be observed during first relapse and relapse after CR. Two hundred and sixty-three patients with MBC were identified who had achieved CR after anthracycline-based combination chemotherapy for first recurrence. From this group, 226 patients had relapse after CR after a minimum follow-up of 13 years. Clinical features of their disease at first relapse and after progression from CR (second relapse) were examined, including disease-free interval (DFI) from diagnosis until first relapse, sites of recurrence, response to subsequent therapy, and survival after progression from CR. There was a significant correlation between duration of CR and survival after progression from CR. Patients who relapsed < 12 months after achieving CR had a median survival of 8.8 months after second relapse, whereas those who relapsed beyond 3 years had a median survival of 21.5 months (p = 0.0034). Neither the duration of CR nor length of survival after second relapse was related to the length of initial DFI. Patients with a short duration of CR (< 12 months) more often experienced second recurrences at multiple sites and in visceral organs (62% and 75%, respectively) than did patients with prolonged CR (> 36 months) (27% and 45%, respectively, p < 0.001). The anatomic location of metastatic disease at the time of first and second relapses was similar within a CR duration group but different among the groups. Short CR duration was associated with more frequent recurrence at visceral sites and also with chemotherapy-resistant second relapse. In conclusion, prolonged CR is associated with long survival after second relapse; however, neither CR duration nor survival after second relapse is related to the length of initial DFI. This suggests that chemotherapy, when it induces CR, may change the pace of disease progression. The tissue pattern of recurrence appears to be similar between first and second relapse, suggesting that the cellular predilection for metastatic sites has been preserved.