Background: Indolent non-Hodgkin lymphomas (iNHL) have relapsing courses after initial therapy. For those who relapse, the response duration to subsequent lines of therapy shortens with time, eventually becoming refractory. Using a large national claims database, this study examined the treatment, mortality and healthcare costs of iNHL patients who relapse after initial therapy. Methods: Patients newly diagnosed with iNHL (i.e., follicular lymphoma, small lymphocytic lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma) during 2004-2013 were identified from the Truven Health MarketScan Commercial and Medicare claims databases. Relapsed or refractory disease (R/R) was defined as those patients relapsing/not responding within 6 months on any combination of alkylating agents (AA) and rituximab (R) as evidenced by having claims indicating a change in treatment. Patients were followed from the start of the new treatment (index date) until death or end of data. Healthcare costs were adjusted to 2013 dollars. Results: Among a total of 254,067 iNHL patients, 1,483 (1.4%) met study criteria for R/R. The average age was 63 (SD 13) and 61% were male. Common comorbidities were: lipometabolic disorders (44%), hypertension (40%), diabetes mellitus (17%), chronic pulmonary disease (15%), cerebrovascular disease (7%) and renal disease (6%). The most common first line regimens were rituximab, cyclophosphamide, doxorubicin and vincristine ± prednisone/ dexamethasone (22%). The mean duration of first-line and second-line therapy was 230 (SD 401) and 369 (SD 544) days, respectively. Among the 45% patients with mortality information, the median survival time from R/R was 5.3 months (mean 16.4, SD 17.7). During the follow up period from the initial date of R/R, the mean annual total medical cost was $170,179 (SD $250,376): 62% outpatient, 34% inpatient and 4% outpatient pharmacy. Conclusions: Patients with R/R iNHL represented a relatively small fraction of all iNHL patients, but had high mortality rate and incurred substantial medical cost.