Purpose/Objective(s): To identify factors associated with the trajectory of acute gastrointestinal (GI) toxicities during pelvic radiation therapy (PRT) in patients with rectal cancer. Materials/Methods: We analyzed 177 consecutive rectal cancer patients treated in 2007-2010. Clinical information including age, gender, stage, chemotherapy, and weekly diarrhea and proctitis grade (CTCAE 3.0) during PRT was recorded. The bowel (BW), rectum, and anal canal (AC) were contoured on treatment planning CT images. Doses to GI structures were calculated using the original treatment plan, and dose-volume parameters were extracted for modeling using CERR software. Fisher’s exact test was used to analyze the effect of clinical factors on weekly Grade 2+ toxicity scores. Logistic regression models were used to test the association between GI toxicity grade and predictors. Results: The median age was 60; 76 (43%) patients were women; 166 (94%) received concurrent 5-FU based chemotherapy; 99 (56%) were treated with intensity modulated radiation therapy (IMRT) and 79 were treated with 3D conformal RT (3DCRT). Grade 2+ diarrhea and proctitis during the entire course of PRT were seen in 44 (25%) and 57 (32%) patients, respectively. A significantly higher rate of Grade 2+ diarrhea was observed in women compared to men during week 4 and 5 of PRT (week 4: 24.2% vs 10.8%, p Z .01; week 5: 33.3% vs 12.2%, p Z .002), as well as in patients treated with 3DCRT vs IMRT (week 4: 22.2% vs 11.5%, p Z .03; week 5: 32.3% vs 10.8%, p Z .001). On multivariate analysis, the normal tissue complication probability (NTCP) model including BW V45 (bowel receiving 45 Gy), female gender, and use of 3DCRT was most predictive of Grade 2+ diarrhea (AUC Z 0.76, Rs Z 0.35, p<.001). Patients treated with IMRT had significantly less bowel volume receiving 45 Gy compared to 3DCRT (10.9% vs 21.7%, p < .001). Women had significantly larger mean irradiated BW volume compared to men (723 cc vs 608 cc, p Z .04; V45: 134 cc vs 73 cc, p < .001). Based on weekly toxicity assessments, patients <60 years of age demonstrated a significantly higher rate of Grade 2+ proctitis compared to patients 60 starting at week 3 (21.1% vs 8.5%, p Z .02; week 4: 34.9% vs 15.8%, p Z .003; week 5: 38.2% vs 23.4%, p Z .03). The model including AC V15, AC minimal dose, and younger age was most predictive of Grade 2+ proctitis (AUC Z 0.67, Rs Z 0.25, p < .001). Conclusions: Women and patients treated with 3DCRT demonstrated higher rates of Grade 2+ diarrhea starting at week 4 of PRT, likely due to the larger irradiated bowel volumes in these populations. Younger patients demonstrated a significantly higher rate of Grade 2+ proctitis starting at week 3. Use of more stringent dosimetric constraints on BW and AC in higher risk patients, such as women and younger patients, should be considered to minimize acute diarrhea and proctitis. Author Disclosure: T. Yang: None. J. Oh: None. C. Son: None. A. Apte: None. A.J. Wu: None. J.O. Deasy: None. K.A. Goodman: None.