Abstract Avocados contain nutrients and phytochemicals that make it promising for cancer prevention, and chemopreventive properties have been demonstrated in prior studies. Prospective studies on avocado consumption and cancer risk have yet to be conducted. This study included data from 45,289 men in the Health Professionals Follow-Up Study (HPFS, 1986–2016) and 67,039 women in the Nurses’ Health Study (NHS, 1986–2014). Avocado consumption was assessed using validated food frequency questionnaires every 4 years. Cox proportional hazards models calculated multivariable HRs and 95% confidence intervals (CI) for associations between avocado consumption and risk of total and site-specific cancers in each cohort. In HPFS, consumption of ≥1 weekly serving of avocados was associated with decreased risk of total (HR, 0.85; 95% CI, 0.80–0.91), colorectal (HR, 0.71; 95% CI, 0.59–0.85), lung (HR, 0.71; 95% CI, 0.57–0.90), and bladder cancer (HR, 0.72; 95% CI, 0.57–0.90). In NHS, avocado consumption was associated with increased risk of breast cancer (HR, 1.21; 95% CI, 1.07–1.37). No associations were observed between avocado consumption and risk of total cancer (HR, 1.06; 95% CI, 0.98–1.14) or other site-specific cancers in NHS. Considering the surprising breast cancer finding, analyses were repeated using data from 93,230 younger women in the parallel NHSII (1991–2017). In NHSII, avocado consumption was not associated with breast cancer risk (HR, 0.93; 95% CI, 0.76–1.13). Overall, avocado consumption may be associated with reduced risk of total and some site-specific cancers in men. The positive association with breast cancer risk in NHS was not seen in the younger NHSII. Prevention Relevance: The results of this prospective study suggest that avocado consumption may be associated with decreased risk of total and some site-specific cancers in men. See related Spotlight, p. 187