Peripheral blood T-lymphocyte subsets were studied serially over a 6 year period in 50 patients with monoclonal gammopathy of unknown significance and multiple myeloma. The results were correlated with clinical status as measured by responsiveness to treatment (response vs. relapse). To allow assessment of the effects of treatment per se upon Tlymphocyte subset levels, patients were studied prior to as well as on and off therapy. After adjustment for treatment effects, the significant correlation (P <0.001) between low percentages of T4-bearing cells and relapse status persisted in all patients. Following multivariate analysis, p,-microglobulin and mprotein values correlated with relapse status, but these correlations were not unexpected since these parameters were often used in association with other clinical and laboratory findings to assess relapse status. The most striking finding of this study was the independent correlation between decreasing percent of T4 levels and increasing probability of relapse (P ~0.003). Specifically, in this study the proportion of subjects with T4 levels <20% who relapsed was 67% regardless of other parameters. The strength of the correlation between the T4 values and relapse may provide insight into the biology of relapsing myeloma as well as adding a clinically useful test for disease assessment.