There are 37 known isotopes of iodine (₅₃I) from ¹⁰⁸I to ¹⁴⁴I; all undergo radioactive decay except ¹²⁷I, which is stable. Iodine is thus a monoisotopic element.

Its longest-lived radioactive isotope, ¹²⁹I, has a half-life of 15.7 million years, which is far too short for it to exist as a primordial nuclide. Cosmogenic sources of ¹²⁹I produce very tiny quantities of it that are too small to affect atomic weight measurements; iodine is thus also a mononuclidic element—one that is found in nature only as a single nuclide. Most ¹²⁹I derived radioactivity on Earth is man-made, an unwanted long-lived byproduct of early nuclear tests and nuclear fission accidents.

All other iodine radioisotopes have half-lives less than 60 days, and four of these are used as tracers and therapeutic agents in medicine. These are ¹²³I, ¹²⁴I, ¹²⁵I, and ¹³¹I. All industrial production of radioactive iodine isotopes involves these four useful radionuclides.

The isotope ¹³⁵I has a half-life less than seven hours, which is too short to be used in biology. Unavoidable in situ production of this isotope is important in nuclear reactor control, as it decays to ¹³⁵Xe, the most powerful known neutron absorber, and the nuclide responsible for the so-called iodine pit phenomenon.

In addition to commercial production, ¹³¹I (half-life 8 days) is one of the common radioactive fission products of nuclear fission, and is thus produced inadvertently in very large amounts inside nuclear reactors. Due to its volatility, short half-life, and high abundance in fission products, ¹³¹I (along with the short-lived iodine isotope ¹³²I, which is produced from the decay of ¹³²Te with a half-life of 3 days) is responsible for the largest part of radioactive contamination during the first week after accidental environmental contamination from the radioactive waste from a nuclear power plant. Thus highly dosed iodine supplements (usually potassium iodide) are given to the populace after nuclear accidents or explosions (and in some cases prior to any such incident as a civil defense mechanism) to reduce the uptake of radioactive iodine compounds by the thyroid before the highly radioactive isotopes have had time to decay.