Background: Malignancy risk with tumour necrosis factor inhibitor (TNFi) therapy remains unclear. Our primary aim was to assess malignancy risk with TNFi therapy in a cohort of Australian patients with rheumatoid arthritis (RA). We also assessed risk in a biologic-naive group. Methods: Demographic data of all RA patients enrolled in the Australian Rheumatology Association Database before 25 October 2010 were matched to national cancer records in July 2010 (linkage complete to 2007). Verified self-reported malignancies occurring between 1 January 2008 and 25 October 2010 were also included in the analysis. Standardised incidence ratios (SIRs) were used to compare malignancy incidence in biologic-naive and TNFi-exposed ARAD participants to the general population using site-, age- and sex-specific rates by calendar year. Rate ratios (RRs) were used to compare malignancy incidence in TNFi-exposed participants to biologic-naive RA patients, and a composite RA cohort that included pre-TNFi person years, both adjusted for age, gender, smoking, methotrexate use and prior malignancy. Results: Forty-four malignancies were reported after 5752 person-years in the TNFi-exposed group (N = 2145) and 32 malignancies were reported after 1682 person-years in the biologic-naive group (N = 803). No overall increased risk of malignancy in TNFi-treated RA patients was found when compared with the general population or with biologic-naive RA patients. Compared to the biologic naive group, without the inclusion of pre-TNFi years in the comparator group, the relative risk of female breast cancer was reduced in TNFi-treated patients (RR 0.17 (95 CI 0.03 to 0.95)). It was no longer significant when adding pre-TNFi years in the comparator group. The risk of melanoma was increased for both biologic naive and TNFi-treated patients when compared with the general population (SIR 2.72 (95 CI 1.13 to 6.53) and SIR 2.03 (95 CI 1.09 to 3.78) respectively). The relative risk of melanoma was not increased in the TNFi-exposed group compared with biologic naive patients (RR 0.54, 95 CI 0.12, 2.40). Inclusion of pre-TNFi person years in the comparator group did not change these results. Conclusions: Malignancy incidence was low in this RA cohort and biologic exposure did not increase the risk of malignancy. Melanoma risk was increased in both TNFi-treated and biologic-naive RA patients compared with the general population suggesting that RA status, and possibly methotrexate exposure, may be responsible.