Evidence obtained using nonimmunosuppressed and newborn mice suggests that the immune response of the host plays a role in the rapid removal of a physiologically isotonic L-form of Streptococcus pyogenes, since its inability to persist in vivo was not due to osmotic lysis. With mice immunosuppressed with methylprednisolone sodium succinate, viability and detection of this L-form by fluorescent antibody was prolonged for at least 2 weeks, the approximate duration of immunosuppression in these mice. However, heat-killed L-form cells only persisted for 3 days in such mice. Therefore, persistence of a viable L-form in these treated mice was not simply due to the lack of removal of L-forms by a compromised host. At no time was there any indication of illness in nonimmunosuppressed or immunosuppressed mice after L-form injection, and all internal organs, when examined macroscopically, remained normal. Thus, overt pathogenesis was not a characteristic of this L-form in a suitable host even when its immune response had been compromised. The microscopic morphology of the L-form after isolation from immunosuppressed mice changed drastically. It was typically micrococcal in appearance and exemplified the cellular variability achievable by this organism in vivo. Also, streptolysin S production was increased markedly by passage of the L-form in immunosuppressed mice. However, M protein, as a cellular component, was not detected serologically, nor was any reformation of a rigid cell wall apparent by electron microscopy after isolation of this streptococcal L-form from such mice.