RNA for protein kinase A regulatory subunit Ialpha (RIalpha) has been measured in tumors from 32 breast cancer patients before and during primary treatment with tamoxifen. Values in pretreatment specimens were significantly higher in tumors subsequently responding to treatment as compared with those not (P = 0.004 by Mann-Whitney U test). Furthermore, whereas levels fell with treatment in 16 of the 24 responding tumors, they did not in any of the 8 tamoxifen-resistant tumors (and indeed rose in 6 cases). These results suggest that measurement of RIalpha mRNA may help in identifying endocrine-dependent breast cancers and provide further evidence of the involvement of the protein kinase A system in response and resistance to tamoxifen treatment.