Objective. To investigate the risk of ovarian malignancy in middle-aged and elderly women with rheumatoid arthritis (RA) and its correlation with disease activity. Methods. 219 middle-aged and elderly (
age
≥
40
) female RA patients who were treated at the Department of Rheumatology and Immunology of the Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine from August 2019 to September 2020 were selected. Their general information such as age and medical history was collected. RA disease activity-related indicators include rheumatoid factor (RF), anticyclic citrullinated peptide antibody (ACPA), ESR, CRP, and ovarian malignancy risk-related indicators including alpha fetoprotein (AFP), carcinoembryonic antigen (CEA), CA125, CA199, and human epididymis protein 4 (HE4) were detected. According to Risk of Ovarian Malignancy Algorithm (ROMA), they were divided into a low-risk group (ROMA-low, premenopausal:
ROMA
≤
11.4
%
, postmenopausal:
ROMA
≤
29.9
%
) and a high-risk group (ROMA-high, premenopausal:
ROMA
>
11.4
%
, postmenopausal:
ROMA
>
29.9
%
) for ovarian malignancy. Meanwhile, according to the DAS28-ESR, they were divided into the general disease activity group (DAS28-
ESR
≤
5.1
) and the high disease activity group (DAS28-
ESR
>
5.1
). SPSS 25.0 software was used to compare the differences among groups and to analyze the correlation between ovarian malignancy risk and RA disease activity. Results. Compared with the ROMA-low group, the levels of RF, ACCP, CDAI, SDAI, DAS28-ESR, and DAS28-CRP in the ROMA-high group were significantly increased (
P
<
0.05
). HE4 and ROMA in the high disease activity group were significantly higher than general disease activity group (
P
<
0.05
). Spearman correlation analysis showed that age (
r
=
0.472
), RF (
r
=
0.221
), ACPA (
r
=
0.156
), CDAI (
r
=
0.226
), SDAI (
r
=
0.221
), DAS28-ESR (
r
=
0.254
), DAS28-CRP (
r
=
0.208
), medications (
r
=
0.189
), and CA199 (
r
=
0.250
) were correlated with ROMA (
P
<
0.05
). Multivariate regression analysis showed that ESR (
OR
=
1.11
), SDAI (
OR
=
1.02
), DAS28-ESR (
OR
=
1.33
), DAS28-CRP (
OR
=
1.26
), and CA199 (
OR
=
1.03
) were independent risk factors for high risk of ovarian malignancy (
P
<
0.05
). Subgroup analysis showed that CA199 is an effect modification factor for DAS28-ESR (
P
<
0.05
). Conclusion. The risk of ovarian malignancy is significantly increased in middle-aged and elderly women with high disease activity with rheumatoid arthritis. In clinical, full attention should be paid to the risk of ovarian malignancy in this population. Screening in time, especially in patients with increased DAS28-ESR and CA199 at the same time, is needed.