Crofelemer is the first US FDA-approved drug for symptomatic relief in HIV-infected persons on antiretroviral therapy (ART) who have non-infectious diarrhea. With the availability of ART, there is increased survival and decrease in gastrointestinal opportunistic infections. However, diarrhea secondary to ART and HIV enteropathy is common in HIV-infected persons. Crofelemer is manufactured from the red latex sap of the Croton lechleri tree in South America. It has a unique mechanism leading to inhibition of chloride ion secretion by blocking chloride channels in the gastrointestinal lumen. This reduces efflux of sodium and water, which in turn reduces the frequency and consistency of diarrhea. Crofelemer is well tolerated due to minimal systemic absorption and has a good safety profile. The availability of crofelemer will likely have a positive impact on the quality of life in HIV-infected persons and also increase compliance to ART.