BACKGROUND: Although physical activity may modify the late effects of childhood cancer treatment, from 20% to 52% of adult survivors are sedentary. The authors of this report sought to identify modifiable factors that influence survivors' participation in physical activity. METHODS: Structural equation modeling of data were derived from the Childhood Cancer Survivors Study of adult survivors (current mean age, 30.98 years; mean years since diagnosis, 23.74; mean age at diagnosis, 9.25 years) who were diagnosed between 1970 and 1986. RESULTS: Approximately 40% of the variance in male survivors' recent participation versus nonparticipation in physical activity was explained directly and/or indirectly by self-reported health fears (P = .01), perceived primary-care physician (PCP) expertise (P = .01), baseline exercise frequency (P < or = .001), education level (P = .01), self-reported stamina (P = .01), cancer-related pain (P < or = .001), fatigue (P < or = .001), age at diagnosis (P = .01), cancer-related anxiety (P < or = .001), motivation (P = .01), affect (P = .01), and discussion of subsequent cancer risk with the PCP (P < or = .001) (N = 256; chi-square test statistic = 53.38; degrees of freedom [df] = 51; P = .38, Comparative Fit Index [CFI] = 1.000; Tucker Lewis Index [TLI] = 1.000; root mean square of approximation [RMSEA] = 0.014; weighted root mean square residual [WRMR] = 0.76). Thirty-one percent of the variance in women' recent physical activity participation was explained directly and/or indirectly by self-reported stamina (P < or = .001), fatigue (P = .01), baseline exercise frequency (P = .01), cancer-related pain (P < or = .001), cancer-related anxiety (P = .01), recency of visits with PCP (<0.001), quality of interaction with the PCP (P = .01), and motivation (P < or = .001; N = 366; chi-square test statistic = 67.52; df = 55; P = .12; CFI = 0.98; TLI = 0.98; RMSEA = 0.025; WRMR = 0.76). CONCLUSIONS: Gender-tailored intervention strategies in which providers specifically target motivation, fear, and affect may support physical activity in childhood cancer survivors.