To investigate the added value of MTX-HCQ combination therapy (CTG) in early RA in a controlled cohort study. MTX monotherapy (MTG) is recommended as (part of) first choice treatment but no head-to-head comparisons are available comparing MTX-HCQ CTG with MTG. RA patients from the Sint Maartenskliniek and Radboudumc Nijmegen who started MTX with or without concomitant HCQ from April 2010 to October 2015 were included. The primary outcome was the between-group ΔDAS28-CRP at 6 months, and secondary outcomes were ΔDAS28-CRP at 12 months, EULAR response at 6 and 12 months, and treatment intensification. Regression modelling was used to correct for confounding. We included 325 patients, with only small between-group differences at baseline. The DAS28-CRP improvement at 6 months was larger in the CTG (Δ = 0.38 (CI: 0.01, 0.76)), and the difference between groups in DAS28-CRP improvement was smaller at 12 months (Δ = 0.22 points (CI:-0.19, -0.62)). At 6 months, a higher percentage of patients had a good EULAR response in the CTG (Δ = 15% (CI: 2.7%, 27%)). This difference was reduced at 12 months (Δ = 6% (CI -6.4%, 19%)). Treatment intensification with conventional synthetic DMARDs was more likely in the MTG (Δ = 31% (CI: -43%, 19%)). The proportion of patients starting biologic DMARD treatment during the observation period was comparable (Δ = 2% (CI: -8%, 12%)). In contrast to indirect comparison review data, MTX-HCQ seems somewhat more effective after 6 months than MTX monotherapy in early RA patients. After 12 months, we observed no significant differences between the two strategies, probably due to treat-to-target efforts.