Objectives To evaluate the 1-year cost-effectiveness between three different initial treatment strategies in autoantibody-negative rheumatoid arthritis(RA-) patients, according to 2010 criteria. Materials and methods For this analysis we selected all RA- patients within the intermediate probability stratum of the tREACH trial. The tREACH had a treat-to-target approach, aiming for low disease activity(DAS<2.4) and treatment adjustments could occur every 3 months. Initial treatment strategies consisted of methotrexate 25mg/week(iMTX), hydroxychloroquine 400mg/day(iHCQ) or an oral glucocorticoids tapering scheme without DMARDs(iGCs). Data on Quality adjusted life-years(QALYs), measured with the EQ-5D-3L, healthcare and productivity costs were used. Results Average QALYs(sd), for iMTX, iHCQ and iGCs were respectively 0.71(0.14), 0.73(0.14) and 0.71(0.15). The average total costs(sd) for iMTX, iHCQ and iGCs were respectively €10.832(14.763), €11.208 (12.801) and €10.502(11.973). Healthcare costs were mainly determined by biological costs, which were significantly lower in the iHCQ group compared to iGCs(p<.05). However, costs due to presenteeism were the highest in the iHCQ group(55%) followed by iMTX(27%) and iGCs(18%). The incremental cost-effectiveness ratios(ICERs) did not differ between treatment strategies. At a willingness-to-pay level of €50.000, the Dutch threshold for reimbursement of medical care, iHCQ had the highest probability(38.7%) of being cost-effective, followed by iGCs(31.1%) and iMTX(30.2%). Conclusions iHCQ had the lowest healthcare and highest productivity costs, resulting in a non-significant ICER. However, iHCQ had the highest chance of being cost-effective at the Dutch WTP-threshold for healthcare reimbursement. Therefore, we believe that iHCQ is a good alternative for iMTX in autoantibody-negative RA patients, but validation is needed. Clinical trial registration number ISRCTN26791028