We examined the role of the natural killer (NK) cell in controlling the survival of embryonic pulmonary fibroblasts in vivo. In vitro, both primary embryonic fibroblasts and an embryonic fibroblast line (10T1/2) were lysed by syngeneic C3H/HeN splenocytes threefold more efficiently than primary adult fibroblasts. The membrane phenotype of the effector cells was typical of NK cells. It was asialo GM1+, Lyt2.1-, Lyt 1.1-, Thy 1.2-. The cytotoxicity of the effector cell could be enhanced by IFN-alpha/beta but was deficient in the C3H/HeJ bg/bg mutant. Iododeoxyuridine (131I-dUrd)-labeled embryonic fibroblasts were injected intravenously into syngeneic mice with either enhanced or deficient NK function and their survival in the lung was quantitated. Enhanced fibroblast survival was detected in the NK deficient C3H/HeJ beige (bg/bg) mutant strain compared to its normal littermate C3H/HeJ (bg/+). A second method of NK depletion by pretreatment with rabbit anti-asialo GM1 antiserum also produced a striking increase in fibroblast survival. Poly(I:C) significantly enhanced the elimination of pulmonary fibroblasts from the lung between 4 and 24 hr after injection. Poly(I:C) did not enhance clearance of pulmonary fibroblasts in the C3H/HeJ (bg/bg) mutant, but did so in the normal littermate C3H/HeJ (bg/+). In conclusion, we have shown that the survival of embryonic pulmonary fibroblasts was inversely correlated with in vivo NK activity suggesting a possible role for this cytotoxic cell in the control of fibroblast growth in vivo.