Timing effects of radioimmunotherapy (RIT) combined with external-beam radiotherapy (RT) were assessed in human colon carcinoma xenografts. Initially, dose effects of fractionated RT and RIT were evaluated separately. Then, 30 Gy RT (10 fractions over 12 days) were combined with three weekly i.v. injections of 200 microCi of 131I-labeled anti-carcinoembryonic antigen monoclonal antibodies in four different treatment schedules. RIT was given either prior to, concurrently, immediately after, or 2 weeks after RT administration. The longest regrowth delay (RD) of 105 days was observed in mice treated by concurrent administration of RT and RIT, whereas the RDs of RT and RIT alone were 34 and 20 days, respectively. The three sequential combination treatments produced significantly shorter RDs ranging from 62 to 70 days. The tumor response represented by the minimal volume (MV) also showed that concurrent administration of RT and RIT gave the best result, with a mean MV of 4.5% as compared to MVs from 26 to 53% for the three sequential treatments. The results were confirmed in a second experiment, in which a RT of 40 Gy was combined with an identical RIT as above (three injections of 200 microCi of 131I-labeled monoclonal antibodies). At comparable toxicity levels, the maximum tolerated RT or RIT alone gave shorter RDs and less tumor shrinkage compared to simultaneous RT+ RIT. These results may be useful for designing clinical protocols of combined RIT and RT.