Although the association between red meat consumption and colorectal cancer (CRC) is well established, the association across subsites of the colon and rectum remains uncertain, as does time of consumption in relation to cancer development. As these relationships are key for understanding the pathogenesis of CRC, they were examined in two large cohorts with repeated dietary measures over time, the Nurses' Health Study (n = 87,108 women, 1980-2010) and Health Professionals Follow-up Study (n = 47,389 men, 1986-2010). Cox proportional hazards regression models generated hazard ratios (HRs) and 95% confidence intervals (CIs), which were pooled by random-effects meta-analysis. In combined cohorts, there were 2,731 CRC cases (1,151 proximal colon, 816 distal colon, and 589 rectum). In pooled analyses, processed red meat was positively associated with CRC risk (per 1 serving/day increase: HR = 1.15, 95% CI: 1.01-1.32; P for trend 0.03) and particularly with distal colon cancer (per 1 serving/day increase; HR = 1.36; 95% CI: 1.09-1.69; P for trend 0.006). Recent consumption of processed meat (within the past 4 years) was not associated with distal cancer. Unprocessed red meat was inversely associated with risk of distal colon cancer and a weak non-significant positive association between unprocessed red meat and proximal cancer was observed (per 1 serving/day increase: distal HR = 0.75; 95% CI: 0.68-0.82; P for trend <0.001; proximal HR = 1.14, 95% CI: 0.92-1.40; P for trend 0.22). Thus, in these two large cohorts of US health professionals, processed meat intake was positively associated with risk of CRC, particularly distal cancer, with little evidence that higher intake of unprocessed red meat substantially increased risk of CRC. Future studies, particularly those with sufficient sample size to assess associations by subsites across the colon are needed to confirm these findings and elucidate potentially distinct mechanisms underlying the relationship between processed meat and subtypes of unprocessed red meat with CRC.