Only recently both the Revised European American Lymphoma (REAL) and World Health Organization (WHO) classifications clearly identified indolent non-follicular non-Hodgkin's lymphoma (NHL) as a distinct group of precise histological entities. Therefore, prognostic models, specifically designed for this NHL subset, are still lacking. In this study, we prospectically evaluated the prognostic criteria proposed by the Gruppo Italiano per lo studio dei linfomi (GISL) to identify patients with an indolent non-progressive clinical course, eligible for a watch and wait policy within this histological subset defined according to stringent criteria of histomorphology and immunophenotype. Fifty-three patients affected with small lymphocytic, marginal zone, lymphoplasmacytic lymphoma and lacking at presentation the following: B symptoms, bulky disease, anemia, thrombocytopenia, diffuse pattern of bone marrow infiltration and short tumor doubling time, were registered in a prospective therapeutic GISL trial and addressed to a watch and wait program. After 41.3 months of median follow-up, the median progression free survival (PFS) was not reached and 73% of cases did not progress. When additional variables were considered, in order to improve the prognostic model, it was evident that LDH level and the number of extranodal sites were of statistical significance in the multivariate analysis. Based on this finding, a prognostic score was devised which was able to further identify a small group of patients more likely to undergo early progression, and thus suitable for immediate treatment. In conclusion, the GISL definition of indolent disease is a reliable tool to design the appropriate therapeutic strategy in this histological setting.