To assess the activity of weekly paclitaxel (wPCT) in pretreated patients with advanced non-small-cell lung cancer (aNSCLC). In 2005, we included wPCT 80 mg/m2 for 6 consecutive weeks, followed by a 2-week interval in our department’s everyday clinical practice guidelines for the second-line (or subsequent) treatment of patients with nonsquamous histologies who have previously received pemetrexed-based treatments and patients with squamous histology. In the absence of clinical evidence of disease progression, patients repeat the pretreatment staging procedures after 16 weeks (two cycles) and, in the absence of disease progression or severe toxicity, continue treatment for a maximum of four courses. Between May 2005 and December 2013, we treated 60 patients (47 in second-line and 13 in third/fourth line), who received a median of two courses (range: 1–4). The most frequent toxicity was grade 1–2 neutropaenia (five patients); only four patients experienced grade 3–4 toxicity. When used as a second-line treatment, wPCT led to a disease control rate of 36.2%, with a median progression-free survival of 3.7 months and a median overall survival of 9.0 months; when used in the third/fourth line, the disease control rate was 41.7%, the median progression-free survival was 5.0 months and the median overall survival was 10.3 months. Our data confirm that wPCT is active and well tolerated in an unselected patient population with aNSCLC and can be considered a valuable alternative to docetaxel in a second-line treatment.