Normalization of the serum-free light-chain ratio (FLCr) with the absence of bone marrow monoclonal plasma cells following achievement of a complete response (CR) to therapy denotes a stringent CR in multiple myeloma (MM), and is associated with improved overall survival (OS). However, its value in patients achieving <CR is not clear. We hypothesized that patients achieving a normalization of FLCr with initial therapy of MM will have an improved outcome, even in the absence of a CR. We retrospectively evaluated 449 patients with newly diagnosed MM with measurable disease at baseline, who did not achieve a CR with initial therapy. One hundred and fifty-three patients (34%) had a normal FLCr, whereas 296 (66%) had an abnormal ratio. Patients with a normal FLCr had a longer progression-free survival (29 vs 16 months, P<0.001) and OS (91 vs 58 months, P<0.001). Normalization of FLCr retained its prognostic value in a multivariable model. Our results suggest an important role for sFLC measurement in disease monitoring even in patients who achieve only a partial response to therapy. Obtaining a normal FLCr confers a favorable prognosis independent from other factors, supporting the inclusion of sFLC in all levels of response criteria.