OBJECTIVE: To compare the incidence of cancer following tumor necrosis factor alpha (TNFalpha) inhibitor therapy to that with commonly used alternative therapies across multiple immune-mediated diseases. METHODS: The Safety Assessment of Biological Therapeutics study used data from 4 sources: national Medicaid and Medicare databases, Tennessee Medicaid, pharmacy benefits plans for Medicare beneficiaries in New Jersey and Pennsylvania, and Kaiser Permanente Northern California. Propensity score-adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) were computed to estimate the relative rates of cancer, comparing those treated with TNFalpha inhibitors to those treated with alternative disease-modifying therapies. The cancer-finding algorithm had a positive predictive value ranging from 31% for any leukemia to 89% for female breast cancer. RESULTS: We included 29,555 patients with rheumatoid arthritis (RA) (13,102 person-years), 6,357 patients with inflammatory bowel disease (1,508 person-years), 1,298 patients with psoriasis (371 person-years), and 2,498 patients with psoriatic arthritis (618 person-years). The incidence of any solid cancer was not elevated in RA (HR 0.80 [95% CI 0.59-1.08]), inflammatory bowel disease (HR 1.42 [95% CI 0.47-4.26]), psoriasis (HR 0.58 [95% CI 0.10-3.31]), or psoriatic arthritis (HR 0.74 [95% CI 0.20-2.76]) during TNFalpha inhibitor therapy compared to disease-specific alternative therapy. Among RA patients, the incidence of any of the 10 most common cancers in the US and of nonmelanoma skin cancer was not increased with TNFalpha inhibitor therapy compared to treatment with comparator drugs. CONCLUSION: Short-term cancer risk was not elevated among patients treated with TNFalpha inhibitor therapy relative to commonly used therapies for immune- mediated chronic inflammatory diseases in this study.