Deficient type I protein kinase A phosphotransferase activity occurs in the T cells of 80% of subjects with systemic lupus erythematosus (SLE). To investigate the mechanism of this deficient isozyme activity, we hypothesized that reduced amounts of type I regulatory (RI) isoform transcripts, RIα and RIβ, may be associated with a diminution of RIα and/or RIβ protein. Sixteen SLE subjects with a mean (±1 SD) SLE disease activity index of 12.4±7.2 were studied. Controls included 16 normal subjects, six subjects with primary Sjögren’s syndrome (SS), and three subjects with SS/SLE overlap. RT-PCR revealed that normal, SS, SS/SLE, and SLE T cells expressed mRNAs for all seven R and catalytic (C) subunit isoforms. Quantification of mRNAs by competitive PCR revealed that the ratio of RIα mRNA to RIβ mRNA in normal T cells was 3.4: 1. In SLE T cells there were 20 and 49% decreases in RIα and RIβ mRNAs (RIβ; p= 0.008), respectively, resulting in an RIα: RIβ mRNA of 5.3: 1. SS/SLE T cells showed a 72.5% decrease in RIβ mRNA compared with normal controls (p= 0.01). Immunoblotting of normal T cell RIα and RIβ proteins revealed a ratio of RIα: RIβ of 3.2: 1. In SLE T cells, there was a 30% decrease in RIα protein (p= 0.002) and a 65% decrease in RIβ protein (p< 0.001), shifting the ratio of RIα: RIβ protein to 6.5: 1. T cells from 25% of SLE subjects lacked any detectable RIβ protein. Analysis of several lupus T cell lines demonstrated a persistent deficiency of both proteins, excluding a potential effect of disease activity. In conclusion, reduced expression of RIα and RIβ transcripts is associated with a decrement in RIα and RIβ proteins and may contribute to deficient type I protein kinase A isozyme activity in SLE T cells.