Background Nonspecific pleuritis (NSP) is a frequent diagnosis after parietal pleural biopsy, but the clinical significance of this finding and need for further follow-up have not been firmly established. Previous reports suggest that 5% to 25% of patients with NSP are subsequently diagnosed with pleural malignancy. Methods Our pathology database was queried for patients with histologic evidence of NSP from January 01, 2001, to December 31, 2012 (n = 413). Patients with less than 1 year of follow-up after biopsy, diagnosis of empyema, tuberculous pleuritis, active systemic connective tissue disease or vasculitis, or active malignancy were excluded (n = 327). The remaining patients were included and their medical records were reviewed. Results Eighty-six patients were included. Mean follow up was 1,824 ± 1,032 days (range, 409 to 4,599 days). Three of the 86 patients with NSP (3.5%) were subsequently diagnosed with pleural malignancy. All 3 patients were found to have mesothelioma with a mean time from biopsies to diagnosis of 205 ± 126 days (range, 64 to 306 days). Twenty-two of 86 patients (25.5%) had a possible identifiable cause of pleural inflammation (benign disease). After exclusion of these 22 patients, the incidence of malignancy was 3 of 64 (4.7%). Conclusions The incidence of subsequent pleural malignancy (mesothelioma) among patients found to have NSP based on pleural biopsy was 3.5%. Occult mesothelioma in patients with NSP will most likely be diagnosed within 1 year of the initial pleural biopsy; therefore, these patients should be followed for a minimum of 1 year to allow for timely detection of occult pleural malignancy.