Background: Numerous studies suggest benefit for heated intra-peritoneal chemotherapy (HIPEC) in colon cancer but the Prodige 7 trial in 265 colon cancer patients randomized to HIPEC or observation after neo-adjuvant chemotherapy (NACT) didn't confirm benefit with median OS of 41.7 vs. 41.2 mos. (p = 0.99) (Proc. ASCO, 2018). One concern is that prior drug exposure selects for drug resistance blunting HIPEC effect. To test the hypothesis we examined the impact of prior chemotherapy on drug resistance in human tumor organoids isolated from colon cancer patients. Methods: Data query identified 111 colorectal cancers (87 colon & 24 rectal) tested for Oxaliplatin sensitivity by ex vivo analysis of programmed cell death (EVA/PCD), a primary culture platform that examines drug induced cell death (apoptotic & non-apoptotic) by morphology, metabolism & histology. Five-point dose response curves interpolated to provide lethal concentration 50% (LC50) were compared by Z score to distribute Oxaliplatin LC50 values around the mean using standard deviation units as the metric of sensitivity or resistance. Of 87 colon 54(62%) were untreated and 33 (38%) treated with 21/33 (64%) having received FOLFOX. To approximate Prodige 7, treated patients were separated by having received FOLFOX < 2 > months before EVA/PCD analysis and also compared Mitomycin (14 vs 41), Irinotecan (18 vs 47) & 5-FU (19 vs. 52) activity to assess cross-resistance. Results: Compared to chemo-naïve, FOLFOX-treated patients were significantly more resistant to Oxaliplatin (P < 0.01) with the degree of resistance increasing significantly for patients who received treatment < 2 months prior to EVA/PCD compared to those with chemotherapy > 2 months prior to EVA/PCD (P < 0.01). Activity for Mitomycin & Irinotecan was not significantly different for chemo-naïve vs. treated patients, but 5 FU was more resistant (P = 0.048) in previously treated. Conclusions: The failure of Prodige 7 to improve survival with HIPEC following NACT may reflect diminished Oxaliplatin activity in patients whose residual disease has been selected for Oxaliplatin & 5FU resistance. Resistance was not observed for Mitomycin or Irinotecan. This suggests that those using HIPEC may i) examine other classes of drugs or drug combinations for IP administration ii) improve the selection of candidates for HIPEC administration or iii) consider HIPEC administration earlier in the course of therapy when chemotherapy-induced drug resistance may be less evident.