We investigated the reasons for switching antiretroviral regimens, an issue rarely addressed in cohort studies.An observed toxicity switch rate (OTSR) was calculated by Poisson regression using the number of days individuals received each individual antiretroviral drug.Of 3333 individuals receiving HAART, a total of 14% of regimens were switched, the majority occurring after 6 months of therapy. Toxicity was the major reason for switching (61%) and there were no major statistically significant differences in OTSR between the protease inhibitor (OTSR 26.4, 95% CI 18.3–37) and non-nucleoside reverse transcriptase inhibitor (OTSR 22.2, 95% CI 13.6–34.4) based regimes. For individual antiretrovirals, stavudine and zidovudine had significantly higher “switch” scores than all other drugs.There were no differences between the major HAART classes in OTSR. We suggest that newer antiretrovirals will require differentiation in terms of longer-term toxicity, as this is the major reason for switching.