Giardia duodenalis is the most common intestinal parasite of humans in the USA, but the risk factors for sporadic (non-outbreak) giardiasis are not well described. The Centers for Disease Control and Prevention and the Colorado and Minnesota public health departments conducted a case-control study to assess risk factors for sporadic giardiasis in the USA. Cases (N = 199) were patients with non-outbreak-associated laboratory-confirmed Giardia infection in Colorado and Minnesota, and controls (N = 381) were matched by age and site. Identified risk factors included international travel (aOR = 13.9; 95% CI 4.9–39.8), drinking water from a river, lake, stream, or spring (aOR = 6.5; 95% CI 2.0–20.6), swimming in a natural body of water (aOR = 3.3; 95% CI 1.5–7.0), male–male sexual behaviour (aOR = 45.7; 95% CI 5.8–362.0), having contact with children in diapers (aOR = 1.6; 95% CI 1.01–2.6), taking antibiotics (aOR = 2.5; 95% CI 1.2–5.0) and having a chronic gastrointestinal condition (aOR = 1.8; 95% CI 1.1–3.0). Eating raw produce was inversely associated with infection (aOR = 0.2; 95% CI 0.1–0.7). Our results highlight the diversity of risk factors for sporadic giardiasis and the importance of non-international-travel-associated risk factors, particularly those involving person-to-person transmission. Prevention measures should focus on reducing risks associated with diaper handling, sexual contact, swimming in untreated water, and drinking untreated water.