Phosphorylation on Y705 is obligatory for STAT3 activation, but full transcriptional activity of this widely expressed protein also requires phosphorylation on S727. We described earlier the STAT3 SA/- mice (SA, S727A allele) on a Black 6 (Bl6) background that showed 75% perinatal lethality and early growth retardation presumably due to the decreased transcription supported by STAT3 S727A. We now report additional analyses of long-term surviving SA/- animals which show no important tissue abnormalities. However, we have found a much greater susceptibility to doxorubicin-induced heart failure in the SA/- mice. Also we introduced the SA allele into strain 129 and found the SA/- mice showed greater susceptibility to LPS-induced toxicity. These results suggest a continued need for normal STAT3 transcriptional activity to resist two different noxious challenges that mimic the conditions necessary to induce adult diseases.